Camille Andy, MD

Evidence Summary

A common female endocrinopathy, PCOS affects 5% to 10% of women. Characterized by anovulation and hyperandrogenism, it often manifests as infertility and irregular menstruation. Metformin and thiazolidinediones are likely effective treatments for these expressions of insulin resistance, but study limitations restrict our ability to clearly define their role.

The most influential systematic review was a meta-analysis that reviewed 13 RCTs including 543 women to determine the effects of metformin on ovarian function in PCOS.^1,2By selecting RCTs, performing precise statistical analysis according to the Cochrane protocols, and clearly stating limitations, this review gives good evidence that metformin modestly increases the odds of ovulation for women with PCOS (odds ratio [OR]=3.88; 95% confidence interval [CI], 2.25–6.69 for metformin vs placebo) and that metformin with clomiphene (Clomid) effectively increases ovulation (OR=4.41; 95% CI, 2.37–8.22) and pregnancy rates (OR=4.40; 95% CI, 1.96–9.85) when compared with clomiphene use alone. When metformin is used as a sole agent, ovulation is achieved in 46% of recipients compared with 24% in the placebo arm (number needed to treat [NNT]=4.4). When metformin and clomiphene are used in combination, 76% of recipients ovulate compared with 42% receiving clomiphene alone (NNT=3.0).

Several problems with recommending metformin as first-line therapy exist: (1) equal or better ovulation rates have been described by using lifestyle interventions to achieve weight loss, (2) there are no long-term studies of the effects of metformin in PCOS patients, and (3) we cannot assess the clinically important outcome of pregnancy rates because the trials did not control for other infertility factors and did not define live births as a primary outcome. In addition, there are no head-to-head trials of metformin vs clomiphene, the standard first-line therapy for ovulation induction. Only 1 study addressed menstrual patterns specifically; they were improved with metformin (OR=12.88; 95% CI, 1.85–89.61).

An additional meta-analysis reports similar results.³ Eight RCTs addressing the use of metformin or clomiphene for treatment of PCOS were reviewed for ovulation and pregnancy rates. Metformin is 50% better than placebo for ovulation induction among infertile PCOS patients (relative risk [RR]=1.50; 95% CI, 1.31–1.99), but this benefit is not necessarily improved with longer duration (>3 months) of therapy (RR=1.37; 95% CI, 1.05–1.79). Also, metformin is beneficial in regulating cycles for fertile PCOS patients with irregular menses (RR=1.45; 95% CI, 1.11–1.90).

The conclusions regarding pregnancy rates and combined therapy with metformin and clomiphene are limited due to small samples, short follow-up time (2–6 months), and study design. An ongoing randomized trial (Pregnancy in Polycystic Ovarian Syndrome: PPOS study) of 768 infertile PCOS patients is investigating effects of metformin vs clomiphene on ovulation induction and achievement of singleton pregnancies. These outcomes should clarify remaining uncertainties regarding appropriate use of metformin.

Finally, a review of 7 RCTs describes the evidence accumulated by well-designed trials and its clinical relevance.⁴ Metformin improves ovulation and menstrual cyclicity but these improvements were variable and modest. On average, 1 additional ovulation is attained in every 5-month interval with metformin treatment; specifically, the baseline of 1 ovulation per 5-month interval increased to 2 ovulations per 5-month interval. Spontaneous ovulation and normal menstruation are achieved rapidly (within 3 months of the start of therapy). These data corroborate the benefits of metformin but place its clinical significance in perspective. For PCOS patients seeking cycle regulation but not pregnancy, oral contraceptives may remain better therapy because metformin does not normalize menses.

Less information exists on the role of TZDs and ovarian function in PCOS. Studies of the most researched drug in the class, troglitazone (Rezulin), report improvements in ovulation rates and metabolic markers of PCOS.^5,6 Troglitazone has been taken off of the market due to hepatotoxicity, but results from a RCT of 40 patients with PCOS reported that the use of pioglitazone (Actos) for 3 months increased normal regular cycles and ovulations over placebo (41.2% vs 5.6%; P<.02).⁷ No liver effects were noted, but caution must be taken since these drugs are pregnancy class C. Two small RCTs studied the use of rosiglitazone (Avandia) in combination with clomiphene and reported improvements in menstrual regularity⁸ (92% with combination therapy achieved improved menstrual cycles vs 68% with rosiglitazone alone; OR=0.185) and both spontaneous and clomiphene-induced ovulation rates (52% of clomiphene-resistant women ovulated after rosiglitazone therapy and 77% vs 33% ovulated with combination therapy vs rosiglitazone alone, P=.04).⁹ Further research is needed to determine the clinical effects of the thiazolidinediones.

Recommendations from Others

The American College of Obstetricians and Gynecologists guideline on diagnosis and management of PCOS reports that interventions that improve insulin sensitivity, including weight loss, use of metformin, and use of TZDs are useful for improving ovulatory frequency for women with PCOS.¹⁰ The recommendation is based on good and consistent scientific evidence (SOR: A). They also note that insulin-sensitizing agents may improve many risk factors for diabetes and cardiovascular disease, but this recommendation is based on limited evidence (SOR: B). Finally, they recommend, based on expert opinion (SOR: C), that caution be used with these agents because their effects on early pregnancy are unknown, even though metformin appears to be safe.

The American Association of Clinical Endocrinologists recommends using metformin 850 mg twice daily to treat the hyperandrogenic state of PCOS.¹¹ The use of TZDs is less clear due to limited evidence and risks of teratogenicity.

Evidence Summary

A common female endocrinopathy, PCOS affects 5% to 10% of women. Characterized by anovulation and hyperandrogenism, it often manifests as infertility and irregular menstruation. Metformin and thiazolidinediones are likely effective treatments for these expressions of insulin resistance, but study limitations restrict our ability to clearly define their role.

The most influential systematic review was a meta-analysis that reviewed 13 RCTs including 543 women to determine the effects of metformin on ovarian function in PCOS.^1,2By selecting RCTs, performing precise statistical analysis according to the Cochrane protocols, and clearly stating limitations, this review gives good evidence that metformin modestly increases the odds of ovulation for women with PCOS (odds ratio [OR]=3.88; 95% confidence interval [CI], 2.25–6.69 for metformin vs placebo) and that metformin with clomiphene (Clomid) effectively increases ovulation (OR=4.41; 95% CI, 2.37–8.22) and pregnancy rates (OR=4.40; 95% CI, 1.96–9.85) when compared with clomiphene use alone. When metformin is used as a sole agent, ovulation is achieved in 46% of recipients compared with 24% in the placebo arm (number needed to treat [NNT]=4.4). When metformin and clomiphene are used in combination, 76% of recipients ovulate compared with 42% receiving clomiphene alone (NNT=3.0).

Several problems with recommending metformin as first-line therapy exist: (1) equal or better ovulation rates have been described by using lifestyle interventions to achieve weight loss, (2) there are no long-term studies of the effects of metformin in PCOS patients, and (3) we cannot assess the clinically important outcome of pregnancy rates because the trials did not control for other infertility factors and did not define live births as a primary outcome. In addition, there are no head-to-head trials of metformin vs clomiphene, the standard first-line therapy for ovulation induction. Only 1 study addressed menstrual patterns specifically; they were improved with metformin (OR=12.88; 95% CI, 1.85–89.61).

An additional meta-analysis reports similar results.³ Eight RCTs addressing the use of metformin or clomiphene for treatment of PCOS were reviewed for ovulation and pregnancy rates. Metformin is 50% better than placebo for ovulation induction among infertile PCOS patients (relative risk [RR]=1.50; 95% CI, 1.31–1.99), but this benefit is not necessarily improved with longer duration (>3 months) of therapy (RR=1.37; 95% CI, 1.05–1.79). Also, metformin is beneficial in regulating cycles for fertile PCOS patients with irregular menses (RR=1.45; 95% CI, 1.11–1.90).

The conclusions regarding pregnancy rates and combined therapy with metformin and clomiphene are limited due to small samples, short follow-up time (2–6 months), and study design. An ongoing randomized trial (Pregnancy in Polycystic Ovarian Syndrome: PPOS study) of 768 infertile PCOS patients is investigating effects of metformin vs clomiphene on ovulation induction and achievement of singleton pregnancies. These outcomes should clarify remaining uncertainties regarding appropriate use of metformin.

Finally, a review of 7 RCTs describes the evidence accumulated by well-designed trials and its clinical relevance.⁴ Metformin improves ovulation and menstrual cyclicity but these improvements were variable and modest. On average, 1 additional ovulation is attained in every 5-month interval with metformin treatment; specifically, the baseline of 1 ovulation per 5-month interval increased to 2 ovulations per 5-month interval. Spontaneous ovulation and normal menstruation are achieved rapidly (within 3 months of the start of therapy). These data corroborate the benefits of metformin but place its clinical significance in perspective. For PCOS patients seeking cycle regulation but not pregnancy, oral contraceptives may remain better therapy because metformin does not normalize menses.

Less information exists on the role of TZDs and ovarian function in PCOS. Studies of the most researched drug in the class, troglitazone (Rezulin), report improvements in ovulation rates and metabolic markers of PCOS.^5,6 Troglitazone has been taken off of the market due to hepatotoxicity, but results from a RCT of 40 patients with PCOS reported that the use of pioglitazone (Actos) for 3 months increased normal regular cycles and ovulations over placebo (41.2% vs 5.6%; P<.02).⁷ No liver effects were noted, but caution must be taken since these drugs are pregnancy class C. Two small RCTs studied the use of rosiglitazone (Avandia) in combination with clomiphene and reported improvements in menstrual regularity⁸ (92% with combination therapy achieved improved menstrual cycles vs 68% with rosiglitazone alone; OR=0.185) and both spontaneous and clomiphene-induced ovulation rates (52% of clomiphene-resistant women ovulated after rosiglitazone therapy and 77% vs 33% ovulated with combination therapy vs rosiglitazone alone, P=.04).⁹ Further research is needed to determine the clinical effects of the thiazolidinediones.

Recommendations from Others

The American College of Obstetricians and Gynecologists guideline on diagnosis and management of PCOS reports that interventions that improve insulin sensitivity, including weight loss, use of metformin, and use of TZDs are useful for improving ovulatory frequency for women with PCOS.¹⁰ The recommendation is based on good and consistent scientific evidence (SOR: A). They also note that insulin-sensitizing agents may improve many risk factors for diabetes and cardiovascular disease, but this recommendation is based on limited evidence (SOR: B). Finally, they recommend, based on expert opinion (SOR: C), that caution be used with these agents because their effects on early pregnancy are unknown, even though metformin appears to be safe.

The American Association of Clinical Endocrinologists recommends using metformin 850 mg twice daily to treat the hyperandrogenic state of PCOS.¹¹ The use of TZDs is less clear due to limited evidence and risks of teratogenicity.

Evidence Summary

A common female endocrinopathy, PCOS affects 5% to 10% of women. Characterized by anovulation and hyperandrogenism, it often manifests as infertility and irregular menstruation. Metformin and thiazolidinediones are likely effective treatments for these expressions of insulin resistance, but study limitations restrict our ability to clearly define their role.

The most influential systematic review was a meta-analysis that reviewed 13 RCTs including 543 women to determine the effects of metformin on ovarian function in PCOS.^1,2By selecting RCTs, performing precise statistical analysis according to the Cochrane protocols, and clearly stating limitations, this review gives good evidence that metformin modestly increases the odds of ovulation for women with PCOS (odds ratio [OR]=3.88; 95% confidence interval [CI], 2.25–6.69 for metformin vs placebo) and that metformin with clomiphene (Clomid) effectively increases ovulation (OR=4.41; 95% CI, 2.37–8.22) and pregnancy rates (OR=4.40; 95% CI, 1.96–9.85) when compared with clomiphene use alone. When metformin is used as a sole agent, ovulation is achieved in 46% of recipients compared with 24% in the placebo arm (number needed to treat [NNT]=4.4). When metformin and clomiphene are used in combination, 76% of recipients ovulate compared with 42% receiving clomiphene alone (NNT=3.0).

Several problems with recommending metformin as first-line therapy exist: (1) equal or better ovulation rates have been described by using lifestyle interventions to achieve weight loss, (2) there are no long-term studies of the effects of metformin in PCOS patients, and (3) we cannot assess the clinically important outcome of pregnancy rates because the trials did not control for other infertility factors and did not define live births as a primary outcome. In addition, there are no head-to-head trials of metformin vs clomiphene, the standard first-line therapy for ovulation induction. Only 1 study addressed menstrual patterns specifically; they were improved with metformin (OR=12.88; 95% CI, 1.85–89.61).

An additional meta-analysis reports similar results.³ Eight RCTs addressing the use of metformin or clomiphene for treatment of PCOS were reviewed for ovulation and pregnancy rates. Metformin is 50% better than placebo for ovulation induction among infertile PCOS patients (relative risk [RR]=1.50; 95% CI, 1.31–1.99), but this benefit is not necessarily improved with longer duration (>3 months) of therapy (RR=1.37; 95% CI, 1.05–1.79). Also, metformin is beneficial in regulating cycles for fertile PCOS patients with irregular menses (RR=1.45; 95% CI, 1.11–1.90).

The conclusions regarding pregnancy rates and combined therapy with metformin and clomiphene are limited due to small samples, short follow-up time (2–6 months), and study design. An ongoing randomized trial (Pregnancy in Polycystic Ovarian Syndrome: PPOS study) of 768 infertile PCOS patients is investigating effects of metformin vs clomiphene on ovulation induction and achievement of singleton pregnancies. These outcomes should clarify remaining uncertainties regarding appropriate use of metformin.

Finally, a review of 7 RCTs describes the evidence accumulated by well-designed trials and its clinical relevance.⁴ Metformin improves ovulation and menstrual cyclicity but these improvements were variable and modest. On average, 1 additional ovulation is attained in every 5-month interval with metformin treatment; specifically, the baseline of 1 ovulation per 5-month interval increased to 2 ovulations per 5-month interval. Spontaneous ovulation and normal menstruation are achieved rapidly (within 3 months of the start of therapy). These data corroborate the benefits of metformin but place its clinical significance in perspective. For PCOS patients seeking cycle regulation but not pregnancy, oral contraceptives may remain better therapy because metformin does not normalize menses.

Less information exists on the role of TZDs and ovarian function in PCOS. Studies of the most researched drug in the class, troglitazone (Rezulin), report improvements in ovulation rates and metabolic markers of PCOS.^5,6 Troglitazone has been taken off of the market due to hepatotoxicity, but results from a RCT of 40 patients with PCOS reported that the use of pioglitazone (Actos) for 3 months increased normal regular cycles and ovulations over placebo (41.2% vs 5.6%; P<.02).⁷ No liver effects were noted, but caution must be taken since these drugs are pregnancy class C. Two small RCTs studied the use of rosiglitazone (Avandia) in combination with clomiphene and reported improvements in menstrual regularity⁸ (92% with combination therapy achieved improved menstrual cycles vs 68% with rosiglitazone alone; OR=0.185) and both spontaneous and clomiphene-induced ovulation rates (52% of clomiphene-resistant women ovulated after rosiglitazone therapy and 77% vs 33% ovulated with combination therapy vs rosiglitazone alone, P=.04).⁹ Further research is needed to determine the clinical effects of the thiazolidinediones.

Recommendations from Others

The American College of Obstetricians and Gynecologists guideline on diagnosis and management of PCOS reports that interventions that improve insulin sensitivity, including weight loss, use of metformin, and use of TZDs are useful for improving ovulatory frequency for women with PCOS.¹⁰ The recommendation is based on good and consistent scientific evidence (SOR: A). They also note that insulin-sensitizing agents may improve many risk factors for diabetes and cardiovascular disease, but this recommendation is based on limited evidence (SOR: B). Finally, they recommend, based on expert opinion (SOR: C), that caution be used with these agents because their effects on early pregnancy are unknown, even though metformin appears to be safe.

The American Association of Clinical Endocrinologists recommends using metformin 850 mg twice daily to treat the hyperandrogenic state of PCOS.¹¹ The use of TZDs is less clear due to limited evidence and risks of teratogenicity.

Evidence summary

The conventional Pap smear is the standard screening test for cervical neoplasia. Despite success, the Pap smear has high false-negative rates due to poor sensitivity (51%; 95% confidence interval [CI], 37%–66%).¹ The ThinPrep was developed to improve sensitivity by providing a monolayer of cells to the cytologist for review. A population-based comparative analysis of good quality shows that the new technology is better at detecting cancer precursors, but other systematic reviews that include less rigorous studies can only suggest it.

The overwhelming problem with most studies is they lack adequate reference standards. Customary criteria for evaluating diagnostic tests require that a “gold standard” reference be used, and that both the abnormal and normal results are validated against it. For cervical cancer screening, the “gold standard” is histology.

Only 1 analysis met the standard criteria. This prospective, population-based study of 8636 women reported that the ThinPrep was significantly more sensitive than the conventional smears at detecting high-grade squamous intraepithelial lesions (HSIL) and cancer, with sensitivity rates of 92.9% and 100% vs 77.8% and 90.9%, respectively (P<.001).² This evidence demonstrates that the ThinPrep is better at detecting cervical cancer.

Several systematic reviews summarize the many studies that compare ThinPrep with the conventional Pap. Unfortunately, conclusions are difficult to interpret. A recent quantitative review implies that the ThinPrep increases cytologic diagnoses of cervical cancer and its precursors.³ A strength of this review is the inclusion of 10 articles with histology as the reference standard. The data from 21,752 patients compared the sensitivity and specificity rates of Thin Prep with conventional Pap for detecting abnormal histology. Sensitivity rates were reported as 76% (ThinPrep) and 68% (conventional), but the differences met statistical significance in only 2 of the included studies. Similarly, the overall specificity rates of the ThinPrep vs conventional Pap was 86% vs 79%, and again the differences did not usually reach statistical significance. The authors hypothesize that widespread use of ThinPrep could potentially detect an additional 162,000 patients with HSIL and 3000 patients with invasive cervical carcinoma.

A large meta-analysis of 25 prospective studies including over 500,000 women reported that ThinPrep increased detection of low-grade squamous intraepithelial lesions (LSIL) (odds ratio [OR]=2.15; 95% CI, 2.05–2.26) and HSIL (OR=2.26; 95% CI, 1.53–1.76), but the conclusions were severely limited by lack of a reference standard and high heterogeneity between study populations.⁴ Another review found insufficient evidence to even judge the new test.⁵

A large evidence review done for the Agency for Healthcare Research and Quality (AHRQ) concluded that the quality of the available literature is poor. Two of the 3 trials reviewed had major methodological flaws that prevented an appropriate comparison of the data to show a modestly higher sensitivity of the ThinPrep.¹ From these reviews, we cannot recommend one technique over the other.

When evaluating a new screening test, cost is important. The AHRQ review¹ and a modeled cost and outcomes analysis⁶ concluded that liquid-based cytology falls within the accepted ranges of cost-effectiveness if used at 3-year screening intervals. Another computer-based model evaluated different triage strategies for ASCUS Pap smears and found that reflex HPV testing provides the same or greater life expectancy benefits and is more cost-effective.⁷ This strategy requires the use of liquid-based cytology. The large ALTS trial supports the use of liquid-based cytology because it has shown HPV testing in patients with ASCUS decreases the need for colposcopy.⁸ Ultimately, when deciding which Pap test is better, many things in addition to sensitivity must be considered.

Recommendations from others

The US Preventive Services Task Force concludes that the evidence is insufficient to recommend for or against the routine use of new technologies to screen for cervical cancer. They acknowledge that ThinPrep may have improved sensitivity over conventional Pap smears but may possibly have lower specificity. The Task Force notes that ThinPrep could be cost-effective with longer screening intervals and can be helpful for the management of ASCUS.⁹

No current screening guidelines specifically recommend newer Pap test technologies in favor of conventional Pap tests. These associations include American Cancer Society, American Academy of Family Physicians, American College of Preventive Medicine, and American College of Gynecology.

Evidence summary

The conventional Pap smear is the standard screening test for cervical neoplasia. Despite success, the Pap smear has high false-negative rates due to poor sensitivity (51%; 95% confidence interval [CI], 37%–66%).¹ The ThinPrep was developed to improve sensitivity by providing a monolayer of cells to the cytologist for review. A population-based comparative analysis of good quality shows that the new technology is better at detecting cancer precursors, but other systematic reviews that include less rigorous studies can only suggest it.

The overwhelming problem with most studies is they lack adequate reference standards. Customary criteria for evaluating diagnostic tests require that a “gold standard” reference be used, and that both the abnormal and normal results are validated against it. For cervical cancer screening, the “gold standard” is histology.

Only 1 analysis met the standard criteria. This prospective, population-based study of 8636 women reported that the ThinPrep was significantly more sensitive than the conventional smears at detecting high-grade squamous intraepithelial lesions (HSIL) and cancer, with sensitivity rates of 92.9% and 100% vs 77.8% and 90.9%, respectively (P<.001).² This evidence demonstrates that the ThinPrep is better at detecting cervical cancer.

Several systematic reviews summarize the many studies that compare ThinPrep with the conventional Pap. Unfortunately, conclusions are difficult to interpret. A recent quantitative review implies that the ThinPrep increases cytologic diagnoses of cervical cancer and its precursors.³ A strength of this review is the inclusion of 10 articles with histology as the reference standard. The data from 21,752 patients compared the sensitivity and specificity rates of Thin Prep with conventional Pap for detecting abnormal histology. Sensitivity rates were reported as 76% (ThinPrep) and 68% (conventional), but the differences met statistical significance in only 2 of the included studies. Similarly, the overall specificity rates of the ThinPrep vs conventional Pap was 86% vs 79%, and again the differences did not usually reach statistical significance. The authors hypothesize that widespread use of ThinPrep could potentially detect an additional 162,000 patients with HSIL and 3000 patients with invasive cervical carcinoma.

A large meta-analysis of 25 prospective studies including over 500,000 women reported that ThinPrep increased detection of low-grade squamous intraepithelial lesions (LSIL) (odds ratio [OR]=2.15; 95% CI, 2.05–2.26) and HSIL (OR=2.26; 95% CI, 1.53–1.76), but the conclusions were severely limited by lack of a reference standard and high heterogeneity between study populations.⁴ Another review found insufficient evidence to even judge the new test.⁵

A large evidence review done for the Agency for Healthcare Research and Quality (AHRQ) concluded that the quality of the available literature is poor. Two of the 3 trials reviewed had major methodological flaws that prevented an appropriate comparison of the data to show a modestly higher sensitivity of the ThinPrep.¹ From these reviews, we cannot recommend one technique over the other.

When evaluating a new screening test, cost is important. The AHRQ review¹ and a modeled cost and outcomes analysis⁶ concluded that liquid-based cytology falls within the accepted ranges of cost-effectiveness if used at 3-year screening intervals. Another computer-based model evaluated different triage strategies for ASCUS Pap smears and found that reflex HPV testing provides the same or greater life expectancy benefits and is more cost-effective.⁷ This strategy requires the use of liquid-based cytology. The large ALTS trial supports the use of liquid-based cytology because it has shown HPV testing in patients with ASCUS decreases the need for colposcopy.⁸ Ultimately, when deciding which Pap test is better, many things in addition to sensitivity must be considered.

Recommendations from others

The US Preventive Services Task Force concludes that the evidence is insufficient to recommend for or against the routine use of new technologies to screen for cervical cancer. They acknowledge that ThinPrep may have improved sensitivity over conventional Pap smears but may possibly have lower specificity. The Task Force notes that ThinPrep could be cost-effective with longer screening intervals and can be helpful for the management of ASCUS.⁹

No current screening guidelines specifically recommend newer Pap test technologies in favor of conventional Pap tests. These associations include American Cancer Society, American Academy of Family Physicians, American College of Preventive Medicine, and American College of Gynecology.

Evidence summary

The conventional Pap smear is the standard screening test for cervical neoplasia. Despite success, the Pap smear has high false-negative rates due to poor sensitivity (51%; 95% confidence interval [CI], 37%–66%).¹ The ThinPrep was developed to improve sensitivity by providing a monolayer of cells to the cytologist for review. A population-based comparative analysis of good quality shows that the new technology is better at detecting cancer precursors, but other systematic reviews that include less rigorous studies can only suggest it.

The overwhelming problem with most studies is they lack adequate reference standards. Customary criteria for evaluating diagnostic tests require that a “gold standard” reference be used, and that both the abnormal and normal results are validated against it. For cervical cancer screening, the “gold standard” is histology.

Only 1 analysis met the standard criteria. This prospective, population-based study of 8636 women reported that the ThinPrep was significantly more sensitive than the conventional smears at detecting high-grade squamous intraepithelial lesions (HSIL) and cancer, with sensitivity rates of 92.9% and 100% vs 77.8% and 90.9%, respectively (P<.001).² This evidence demonstrates that the ThinPrep is better at detecting cervical cancer.

Several systematic reviews summarize the many studies that compare ThinPrep with the conventional Pap. Unfortunately, conclusions are difficult to interpret. A recent quantitative review implies that the ThinPrep increases cytologic diagnoses of cervical cancer and its precursors.³ A strength of this review is the inclusion of 10 articles with histology as the reference standard. The data from 21,752 patients compared the sensitivity and specificity rates of Thin Prep with conventional Pap for detecting abnormal histology. Sensitivity rates were reported as 76% (ThinPrep) and 68% (conventional), but the differences met statistical significance in only 2 of the included studies. Similarly, the overall specificity rates of the ThinPrep vs conventional Pap was 86% vs 79%, and again the differences did not usually reach statistical significance. The authors hypothesize that widespread use of ThinPrep could potentially detect an additional 162,000 patients with HSIL and 3000 patients with invasive cervical carcinoma.

A large meta-analysis of 25 prospective studies including over 500,000 women reported that ThinPrep increased detection of low-grade squamous intraepithelial lesions (LSIL) (odds ratio [OR]=2.15; 95% CI, 2.05–2.26) and HSIL (OR=2.26; 95% CI, 1.53–1.76), but the conclusions were severely limited by lack of a reference standard and high heterogeneity between study populations.⁴ Another review found insufficient evidence to even judge the new test.⁵

A large evidence review done for the Agency for Healthcare Research and Quality (AHRQ) concluded that the quality of the available literature is poor. Two of the 3 trials reviewed had major methodological flaws that prevented an appropriate comparison of the data to show a modestly higher sensitivity of the ThinPrep.¹ From these reviews, we cannot recommend one technique over the other.

When evaluating a new screening test, cost is important. The AHRQ review¹ and a modeled cost and outcomes analysis⁶ concluded that liquid-based cytology falls within the accepted ranges of cost-effectiveness if used at 3-year screening intervals. Another computer-based model evaluated different triage strategies for ASCUS Pap smears and found that reflex HPV testing provides the same or greater life expectancy benefits and is more cost-effective.⁷ This strategy requires the use of liquid-based cytology. The large ALTS trial supports the use of liquid-based cytology because it has shown HPV testing in patients with ASCUS decreases the need for colposcopy.⁸ Ultimately, when deciding which Pap test is better, many things in addition to sensitivity must be considered.

Recommendations from others

The US Preventive Services Task Force concludes that the evidence is insufficient to recommend for or against the routine use of new technologies to screen for cervical cancer. They acknowledge that ThinPrep may have improved sensitivity over conventional Pap smears but may possibly have lower specificity. The Task Force notes that ThinPrep could be cost-effective with longer screening intervals and can be helpful for the management of ASCUS.⁹

No current screening guidelines specifically recommend newer Pap test technologies in favor of conventional Pap tests. These associations include American Cancer Society, American Academy of Family Physicians, American College of Preventive Medicine, and American College of Gynecology.

Evidence summary

A meta-analysis of 16 RCTs compared the efficacy of intranasal steroids and oral antihistamines for alleviating nasal, eye, and global allergy symptoms.¹ Intranasal steroids were superior to oral antihistamines for all patient-oriented nasal symptom and global symptom ratings. Eye symptom scores and adverse events were similar in each treatment group.

Several large RCTs have addressed whether combining the 2 classes of drugs would achieve greater symptom control. Only 1 study² found combination therapy to be superior. This RCT compared beclomethasone dipropionate with loratadine or placebo daily in 154 patients.² Total symptom scores were better for the combination group mainly due to improved relief from ocular symptoms.

Fluticasone propionate aqueous nasal spray (FPANS) was evaluated alone and in combination with cetirizine in a multicenter double-blind study of 454 patients.³ The mean symptom scores for nasal and eye symptoms were not significantly different between the 2 groups. A more recent RCT had similar results when comparing FPANS with loratadine and with combined therapy.⁴ This double-blinded placebo-controlled trial, which included 600 patients, measured patient- and clinician-rated total symptom scores, individual nasal symptom scores, and overall evaluations after 7 and 14 days of therapy. Although the symptom scores for the FPANS group were significantly lower than those in the loratadine and placebo groups, no significant difference in scores was found between the FPANS and combined groups. The results were the same for the quality-of-life questionnaire scores. In an RCT of 106 patients, budesonide nasal spray’s efficacy was tested against terfenadine alone and in combination; the nasal steroid alone was more effective than the histamine.⁵ Combining the 2 drugs yielded no significant improvements.

The newer nasal steroids such as fluticasone may be more effective because of their stronger affinities to glucocorticoid receptors, but no clinical evidence confirms this hypothesis.⁶

TABLE
Intranasal steroids for treating allergic rhinitis

Recommendations from others

The Joint Task Force on Practice Parameters in Allergy, Asthma, and Immunology recommends second-generation oral antihistamines for first-line therapy, but notes that nasal steroids are the most effective medication class for controlling allergy symptoms.⁷ The task force states that combination drug therapy may be tried. A monograph from the American Academy of Family Physicians notes the lack of consensus guidelines for first-line therapy and recommends that treatment be individualized.⁸ It states that combination therapy may be tried if monotherapy fails.

Clinical Commentaries by Tsveti Markova, MD, and John W. Tipton, MD, at http://www.FPIN.org.

Evidence summary

A meta-analysis of 16 RCTs compared the efficacy of intranasal steroids and oral antihistamines for alleviating nasal, eye, and global allergy symptoms.¹ Intranasal steroids were superior to oral antihistamines for all patient-oriented nasal symptom and global symptom ratings. Eye symptom scores and adverse events were similar in each treatment group.

Several large RCTs have addressed whether combining the 2 classes of drugs would achieve greater symptom control. Only 1 study² found combination therapy to be superior. This RCT compared beclomethasone dipropionate with loratadine or placebo daily in 154 patients.² Total symptom scores were better for the combination group mainly due to improved relief from ocular symptoms.

Fluticasone propionate aqueous nasal spray (FPANS) was evaluated alone and in combination with cetirizine in a multicenter double-blind study of 454 patients.³ The mean symptom scores for nasal and eye symptoms were not significantly different between the 2 groups. A more recent RCT had similar results when comparing FPANS with loratadine and with combined therapy.⁴ This double-blinded placebo-controlled trial, which included 600 patients, measured patient- and clinician-rated total symptom scores, individual nasal symptom scores, and overall evaluations after 7 and 14 days of therapy. Although the symptom scores for the FPANS group were significantly lower than those in the loratadine and placebo groups, no significant difference in scores was found between the FPANS and combined groups. The results were the same for the quality-of-life questionnaire scores. In an RCT of 106 patients, budesonide nasal spray’s efficacy was tested against terfenadine alone and in combination; the nasal steroid alone was more effective than the histamine.⁵ Combining the 2 drugs yielded no significant improvements.

The newer nasal steroids such as fluticasone may be more effective because of their stronger affinities to glucocorticoid receptors, but no clinical evidence confirms this hypothesis.⁶

TABLE
Intranasal steroids for treating allergic rhinitis

Recommendations from others

The Joint Task Force on Practice Parameters in Allergy, Asthma, and Immunology recommends second-generation oral antihistamines for first-line therapy, but notes that nasal steroids are the most effective medication class for controlling allergy symptoms.⁷ The task force states that combination drug therapy may be tried. A monograph from the American Academy of Family Physicians notes the lack of consensus guidelines for first-line therapy and recommends that treatment be individualized.⁸ It states that combination therapy may be tried if monotherapy fails.

Clinical Commentaries by Tsveti Markova, MD, and John W. Tipton, MD, at http://www.FPIN.org.

Evidence summary

A meta-analysis of 16 RCTs compared the efficacy of intranasal steroids and oral antihistamines for alleviating nasal, eye, and global allergy symptoms.¹ Intranasal steroids were superior to oral antihistamines for all patient-oriented nasal symptom and global symptom ratings. Eye symptom scores and adverse events were similar in each treatment group.

Several large RCTs have addressed whether combining the 2 classes of drugs would achieve greater symptom control. Only 1 study² found combination therapy to be superior. This RCT compared beclomethasone dipropionate with loratadine or placebo daily in 154 patients.² Total symptom scores were better for the combination group mainly due to improved relief from ocular symptoms.

Fluticasone propionate aqueous nasal spray (FPANS) was evaluated alone and in combination with cetirizine in a multicenter double-blind study of 454 patients.³ The mean symptom scores for nasal and eye symptoms were not significantly different between the 2 groups. A more recent RCT had similar results when comparing FPANS with loratadine and with combined therapy.⁴ This double-blinded placebo-controlled trial, which included 600 patients, measured patient- and clinician-rated total symptom scores, individual nasal symptom scores, and overall evaluations after 7 and 14 days of therapy. Although the symptom scores for the FPANS group were significantly lower than those in the loratadine and placebo groups, no significant difference in scores was found between the FPANS and combined groups. The results were the same for the quality-of-life questionnaire scores. In an RCT of 106 patients, budesonide nasal spray’s efficacy was tested against terfenadine alone and in combination; the nasal steroid alone was more effective than the histamine.⁵ Combining the 2 drugs yielded no significant improvements.

The newer nasal steroids such as fluticasone may be more effective because of their stronger affinities to glucocorticoid receptors, but no clinical evidence confirms this hypothesis.⁶

TABLE
Intranasal steroids for treating allergic rhinitis

Recommendations from others

The Joint Task Force on Practice Parameters in Allergy, Asthma, and Immunology recommends second-generation oral antihistamines for first-line therapy, but notes that nasal steroids are the most effective medication class for controlling allergy symptoms.⁷ The task force states that combination drug therapy may be tried. A monograph from the American Academy of Family Physicians notes the lack of consensus guidelines for first-line therapy and recommends that treatment be individualized.⁸ It states that combination therapy may be tried if monotherapy fails.

Clinical Commentaries by Tsveti Markova, MD, and John W. Tipton, MD, at http://www.FPIN.org.

ABSTRACT

BACKGROUND: Because strong evidence supports the association between cervical length and preterm delivery and perinatal morbidity, transvaginal ultrasound (TVUS) has been used to identify patients with premature cervical change who may benefit from therapeutic cerclage placement. Observational studies report conflicting results regarding the benefits of therapeutic cerclage. Few randomized trials regarding the efficacy of cerclage therapy have been reported.

POPULATION STUDIED: This study enrolled 113 women from an urban outpatient perinatal testing center that had cervical changes identified by TVUS during the second trimester of pregnancy. Specific changes were dilation of the internal os and either (1) prolapse of membranes of at least 25% of the total cervical length or (2) a distal cervical length of less than 2.5 cm. Subjects were excluded if they had membrane prolapse beyond the external os or any other contraindication to cerclage. All participants were similar with regard to age, risk factors for preterm labor, and history of preterm deliveries. However, patients in the no-cerclage group tended to have an increased rate of second-trimester deliveries (12.1 vs 27.3, P = .07).

STUDY DESIGN AND VALIDITY: This was an open randomized controlled trial. Participants with cervical changes were randomized to receive either McDonald cerclage (n = 55) or no cerclage (n = 58). Before randomization, all patients received amniocentesis, multiple urogenital cultures, indomethacin, and clindamycin. All subjects were treated identically (including serial ultrasonography and modified bed rest) after the intervention. Routine prenatal care continued and cerclage was removed at 36 weeks’ gestational age or for any of the following reasons: rupture of membranes, preterm labor refractory to tocolytic therapy, or other indication for delivery. Analysis was done by intention to treat. The authors developed a stepwise logistic regression model to analyze dependent and independent variables. It is uncertain whether allocation assignment to treatment group was concealed.

OUTCOMES MEASURED: The primary outcomes measured were gestational age at delivery and neonatal morbidity, defined as none, minimal, severe, or death. The authors analyzed a number of other variables to determine any associations with the primary outcomes but did not address cost effectiveness or patient satisfaction.

RESULTS: There were no statistical differences in the primary outcomes of gestational age at delivery of less than 34 weeks’ gestation (34.9 vs 36.2, P = .8) or perinatal morbidity, reported only as perinatal death (12.7 vs 11.9, P = .9). The regression model analysis identified preterm labor, chorioamnionitis, and abruption as significant risk factors associated with the primary outcomes.

ABSTRACT

BACKGROUND: Because strong evidence supports the association between cervical length and preterm delivery and perinatal morbidity, transvaginal ultrasound (TVUS) has been used to identify patients with premature cervical change who may benefit from therapeutic cerclage placement. Observational studies report conflicting results regarding the benefits of therapeutic cerclage. Few randomized trials regarding the efficacy of cerclage therapy have been reported.

POPULATION STUDIED: This study enrolled 113 women from an urban outpatient perinatal testing center that had cervical changes identified by TVUS during the second trimester of pregnancy. Specific changes were dilation of the internal os and either (1) prolapse of membranes of at least 25% of the total cervical length or (2) a distal cervical length of less than 2.5 cm. Subjects were excluded if they had membrane prolapse beyond the external os or any other contraindication to cerclage. All participants were similar with regard to age, risk factors for preterm labor, and history of preterm deliveries. However, patients in the no-cerclage group tended to have an increased rate of second-trimester deliveries (12.1 vs 27.3, P = .07).

STUDY DESIGN AND VALIDITY: This was an open randomized controlled trial. Participants with cervical changes were randomized to receive either McDonald cerclage (n = 55) or no cerclage (n = 58). Before randomization, all patients received amniocentesis, multiple urogenital cultures, indomethacin, and clindamycin. All subjects were treated identically (including serial ultrasonography and modified bed rest) after the intervention. Routine prenatal care continued and cerclage was removed at 36 weeks’ gestational age or for any of the following reasons: rupture of membranes, preterm labor refractory to tocolytic therapy, or other indication for delivery. Analysis was done by intention to treat. The authors developed a stepwise logistic regression model to analyze dependent and independent variables. It is uncertain whether allocation assignment to treatment group was concealed.

OUTCOMES MEASURED: The primary outcomes measured were gestational age at delivery and neonatal morbidity, defined as none, minimal, severe, or death. The authors analyzed a number of other variables to determine any associations with the primary outcomes but did not address cost effectiveness or patient satisfaction.

RESULTS: There were no statistical differences in the primary outcomes of gestational age at delivery of less than 34 weeks’ gestation (34.9 vs 36.2, P = .8) or perinatal morbidity, reported only as perinatal death (12.7 vs 11.9, P = .9). The regression model analysis identified preterm labor, chorioamnionitis, and abruption as significant risk factors associated with the primary outcomes.

ABSTRACT

BACKGROUND: Because strong evidence supports the association between cervical length and preterm delivery and perinatal morbidity, transvaginal ultrasound (TVUS) has been used to identify patients with premature cervical change who may benefit from therapeutic cerclage placement. Observational studies report conflicting results regarding the benefits of therapeutic cerclage. Few randomized trials regarding the efficacy of cerclage therapy have been reported.

POPULATION STUDIED: This study enrolled 113 women from an urban outpatient perinatal testing center that had cervical changes identified by TVUS during the second trimester of pregnancy. Specific changes were dilation of the internal os and either (1) prolapse of membranes of at least 25% of the total cervical length or (2) a distal cervical length of less than 2.5 cm. Subjects were excluded if they had membrane prolapse beyond the external os or any other contraindication to cerclage. All participants were similar with regard to age, risk factors for preterm labor, and history of preterm deliveries. However, patients in the no-cerclage group tended to have an increased rate of second-trimester deliveries (12.1 vs 27.3, P = .07).

STUDY DESIGN AND VALIDITY: This was an open randomized controlled trial. Participants with cervical changes were randomized to receive either McDonald cerclage (n = 55) or no cerclage (n = 58). Before randomization, all patients received amniocentesis, multiple urogenital cultures, indomethacin, and clindamycin. All subjects were treated identically (including serial ultrasonography and modified bed rest) after the intervention. Routine prenatal care continued and cerclage was removed at 36 weeks’ gestational age or for any of the following reasons: rupture of membranes, preterm labor refractory to tocolytic therapy, or other indication for delivery. Analysis was done by intention to treat. The authors developed a stepwise logistic regression model to analyze dependent and independent variables. It is uncertain whether allocation assignment to treatment group was concealed.

OUTCOMES MEASURED: The primary outcomes measured were gestational age at delivery and neonatal morbidity, defined as none, minimal, severe, or death. The authors analyzed a number of other variables to determine any associations with the primary outcomes but did not address cost effectiveness or patient satisfaction.

RESULTS: There were no statistical differences in the primary outcomes of gestational age at delivery of less than 34 weeks’ gestation (34.9 vs 36.2, P = .8) or perinatal morbidity, reported only as perinatal death (12.7 vs 11.9, P = .9). The regression model analysis identified preterm labor, chorioamnionitis, and abruption as significant risk factors associated with the primary outcomes.

BACKGROUND: HRT relieves vasomotor symptoms in postmenopausal women but is associated with adverse side effects. Low-dose HRT has been shown to reduce side effects, but its effectiveness for the relief of vasomotor symptoms is uncertain.

POPULATION STUDIED: A total of 241 predominantly white (88%) women who reported at least 7 daily moderate-to-severe baseline hot flushes or at least 50 total hot flushes per week were evaluated. The subjects were chosen from 2673 healthy postmenopausal women who were aged 40 to 65 years, had intact uteruses, and were within 20% of normal body weight. Exclusion criteria included use of hormones or medicines known to affect vasomotor symptoms. This population is similar to the healthy postmenopausal patients of many family physicians.

STUDY DESIGN AND VALIDITY: The participants were randomized in a double-blind manner (concealed allocation assignment) to 1 of 8 treatment groups including combinations of either placebo or conjugated equine estrogens (CEE) with or without medroxyprogesterone (MPA) for 1 year (13 cycles of 28 days each). Daily dosing regimens were: CEE 0.625 mg, CEE 0.625 mg and MPA 2.5 mg, CEE 0.45 mg, CEE 0.45 mg and MPA 2.5 mg, CEE 0.45 mg and MPA 1.5 mg, CEE 0.3 mg, CEE 0.3 mg and MPA 1.5 mg, or placebo. The patients recorded the number and severity of hot flushes on daily diary cards that were collected at office visits scheduled for cycle 3, 6, 9, and 13. The mean daily number and the mean daily severity of hot flushes were calculated and compared using paired t tests. Vaginal atrophy was assessed by a vaginal maturation index (VMI) that was performed twice. This analysis was done in an intention-to-treat population.Unfortunately, data presentation was ambiguous: No numerical data or confidence intervals were given, making it difficult to both quantify the decrease in number and severity of hot flushes in the treatment groups and to assess clinical significance of the results. The lack of correlation between VMI and symptoms of vaginal atrophy make this information clinically meaningless. Finally, the withdrawal rate of the evaluable population was not given.

OUTCOME MEASURED: The number and severity of hot flushes experienced and the change of the VMIs over the 13 cycles were measured. Cost, quality-of-life improvement, and symptoms of vaginal atrophy were not addressed.

RESULTS: The baseline characteristics of the women in the various groups were similar. All active treatment groups experienced a decrease in the mean number of daily hot flushes when compared with the placebo group (P <.05), and there was no difference observed between the standard dose of HRT therapy (CEE 0.625 mg/MPA 2.5 mg) and low-dose HRT. The CEE 0.625 mg group reported fewer hot flushes than the other lower estrogen-only groups (P <.05). Results were similar for the mean daily severity of hot flushes. All active treatment groups experienced a decrease in severity of hot flushes compared with placebo (P <.05), and there was no significant difference between the standard dose and the lower dose combinations. The CEE 0.625 mg group experienced less severe hot flushes than the other lower estrogen-only treated groups by cycle 3 (P <.05). All active treatment groups reported a significant increase in VMI at cycle 6 and 13 when compared with placebo (P <.001).

BACKGROUND: HRT relieves vasomotor symptoms in postmenopausal women but is associated with adverse side effects. Low-dose HRT has been shown to reduce side effects, but its effectiveness for the relief of vasomotor symptoms is uncertain.

POPULATION STUDIED: A total of 241 predominantly white (88%) women who reported at least 7 daily moderate-to-severe baseline hot flushes or at least 50 total hot flushes per week were evaluated. The subjects were chosen from 2673 healthy postmenopausal women who were aged 40 to 65 years, had intact uteruses, and were within 20% of normal body weight. Exclusion criteria included use of hormones or medicines known to affect vasomotor symptoms. This population is similar to the healthy postmenopausal patients of many family physicians.

STUDY DESIGN AND VALIDITY: The participants were randomized in a double-blind manner (concealed allocation assignment) to 1 of 8 treatment groups including combinations of either placebo or conjugated equine estrogens (CEE) with or without medroxyprogesterone (MPA) for 1 year (13 cycles of 28 days each). Daily dosing regimens were: CEE 0.625 mg, CEE 0.625 mg and MPA 2.5 mg, CEE 0.45 mg, CEE 0.45 mg and MPA 2.5 mg, CEE 0.45 mg and MPA 1.5 mg, CEE 0.3 mg, CEE 0.3 mg and MPA 1.5 mg, or placebo. The patients recorded the number and severity of hot flushes on daily diary cards that were collected at office visits scheduled for cycle 3, 6, 9, and 13. The mean daily number and the mean daily severity of hot flushes were calculated and compared using paired t tests. Vaginal atrophy was assessed by a vaginal maturation index (VMI) that was performed twice. This analysis was done in an intention-to-treat population.Unfortunately, data presentation was ambiguous: No numerical data or confidence intervals were given, making it difficult to both quantify the decrease in number and severity of hot flushes in the treatment groups and to assess clinical significance of the results. The lack of correlation between VMI and symptoms of vaginal atrophy make this information clinically meaningless. Finally, the withdrawal rate of the evaluable population was not given.

OUTCOME MEASURED: The number and severity of hot flushes experienced and the change of the VMIs over the 13 cycles were measured. Cost, quality-of-life improvement, and symptoms of vaginal atrophy were not addressed.

RESULTS: The baseline characteristics of the women in the various groups were similar. All active treatment groups experienced a decrease in the mean number of daily hot flushes when compared with the placebo group (P <.05), and there was no difference observed between the standard dose of HRT therapy (CEE 0.625 mg/MPA 2.5 mg) and low-dose HRT. The CEE 0.625 mg group reported fewer hot flushes than the other lower estrogen-only groups (P <.05). Results were similar for the mean daily severity of hot flushes. All active treatment groups experienced a decrease in severity of hot flushes compared with placebo (P <.05), and there was no significant difference between the standard dose and the lower dose combinations. The CEE 0.625 mg group experienced less severe hot flushes than the other lower estrogen-only treated groups by cycle 3 (P <.05). All active treatment groups reported a significant increase in VMI at cycle 6 and 13 when compared with placebo (P <.001).

BACKGROUND: HRT relieves vasomotor symptoms in postmenopausal women but is associated with adverse side effects. Low-dose HRT has been shown to reduce side effects, but its effectiveness for the relief of vasomotor symptoms is uncertain.

POPULATION STUDIED: A total of 241 predominantly white (88%) women who reported at least 7 daily moderate-to-severe baseline hot flushes or at least 50 total hot flushes per week were evaluated. The subjects were chosen from 2673 healthy postmenopausal women who were aged 40 to 65 years, had intact uteruses, and were within 20% of normal body weight. Exclusion criteria included use of hormones or medicines known to affect vasomotor symptoms. This population is similar to the healthy postmenopausal patients of many family physicians.

STUDY DESIGN AND VALIDITY: The participants were randomized in a double-blind manner (concealed allocation assignment) to 1 of 8 treatment groups including combinations of either placebo or conjugated equine estrogens (CEE) with or without medroxyprogesterone (MPA) for 1 year (13 cycles of 28 days each). Daily dosing regimens were: CEE 0.625 mg, CEE 0.625 mg and MPA 2.5 mg, CEE 0.45 mg, CEE 0.45 mg and MPA 2.5 mg, CEE 0.45 mg and MPA 1.5 mg, CEE 0.3 mg, CEE 0.3 mg and MPA 1.5 mg, or placebo. The patients recorded the number and severity of hot flushes on daily diary cards that were collected at office visits scheduled for cycle 3, 6, 9, and 13. The mean daily number and the mean daily severity of hot flushes were calculated and compared using paired t tests. Vaginal atrophy was assessed by a vaginal maturation index (VMI) that was performed twice. This analysis was done in an intention-to-treat population.Unfortunately, data presentation was ambiguous: No numerical data or confidence intervals were given, making it difficult to both quantify the decrease in number and severity of hot flushes in the treatment groups and to assess clinical significance of the results. The lack of correlation between VMI and symptoms of vaginal atrophy make this information clinically meaningless. Finally, the withdrawal rate of the evaluable population was not given.

OUTCOME MEASURED: The number and severity of hot flushes experienced and the change of the VMIs over the 13 cycles were measured. Cost, quality-of-life improvement, and symptoms of vaginal atrophy were not addressed.

RESULTS: The baseline characteristics of the women in the various groups were similar. All active treatment groups experienced a decrease in the mean number of daily hot flushes when compared with the placebo group (P <.05), and there was no difference observed between the standard dose of HRT therapy (CEE 0.625 mg/MPA 2.5 mg) and low-dose HRT. The CEE 0.625 mg group reported fewer hot flushes than the other lower estrogen-only groups (P <.05). Results were similar for the mean daily severity of hot flushes. All active treatment groups experienced a decrease in severity of hot flushes compared with placebo (P <.05), and there was no significant difference between the standard dose and the lower dose combinations. The CEE 0.625 mg group experienced less severe hot flushes than the other lower estrogen-only treated groups by cycle 3 (P <.05). All active treatment groups reported a significant increase in VMI at cycle 6 and 13 when compared with placebo (P <.001).