Expert Commentary

A. No. However, these two studies found some evidence that use of selective serotonin-reuptake inhibitors (SSRIs) at the time of conception or during pregnancy is associated with anencephaly, craniosynostosis, and omphalocele—although the absolute risk was very low and the association needs to be confirmed by further study. These studies also found a significant association between specific SSRIs and birth defects, such as paroxetine (Paxil) and right ventricular outflow tract obstruction, but, again, the absolute risk was very low and the birth defects in question are rare.

Expert Commentary

Because depression is fairly common among women of reproductive age and is often treated with SSRIs, the issue of teratogenicity is important. Earlier investigations suggested that use of these drugs—particularly paroxetine—during early pregnancy increases the risk of heart defects. These two ongoing case-control studies help clarify the relationship between prenatal use of SSRIs and birth defects, although the issue still has not been addressed definitively.

Both studies involved large populations

The first study was conducted by investigators from the Centers for Disease Control and Prevention and the University of British Columbia. It involved 9,622 infants with major birth defects and 4,092 control infants, all of whom were born between 1997 and 2002. Case infants were identified using birth-defect surveillance systems in eight US states, and control infants were randomly selected from the same regions. A woman was considered exposed to an SSRI if she used any of the medications from 1 month before to 3 months after conception.

Investigators found no significant association between maternal SSRI use in early pregnancy and most categories of birth defects, including congenital heart defects. However, they found a significant association between maternal SSRI use and anencephaly (odds ratio [OR], 2.4; 95% confidence interval [CI], 1.1–5.1), craniosynostosis (OR, 2.5; 95% CI, 1.5–4.0), and omphalocele (OR, 2.8; 95% CI, 1.3–5.7). Use of paroxetine correlated with higher pooled ORs for these three birth defects, as well as a significantly increased risk of right ventricular outflow tract obstruction.

The study by Louik and associates was funded by the National Institutes of Health and GlaxoSmithKline, the manufacturer of Paxil. It involved 9,849 infants with major birth defects and 5,860 control infants, all of whom were born in the United States or Canada between 1993 and 2005. All infants in the case and control groups were identified through their participation in the Slone Epidemiology Center Birth Defects Study, a continuing analysis of medication use in pregnancy. Because Louik and colleagues focused on first-trimester use of SSRIs, exposure was defined as use of any SSRI from 28 days before the last menstrual period through the fourth lunar month (112 days after the last menstrual period.

Use of SSRIs overall was not associated with heart defects, craniosynostosis, or omphalocele, but a significant association was found between paroxetine use and right ventricular outflow tract obstruction (based on 6 exposed subjects) and between septal defects and sertraline use (based on 13 exposed subjects).

TABLE

SSRIs in pregnancy: How they stack up

ANTIDEPRESSANT	ADVANTAGES	DISADVANTAGES*	PREGNANCY CATEGORY
Citalopram (Celexa)	Few interactions with other medications	No behavioral studies in human pregnancy	C
Escitalopram (Lexapro)	Few interactions with other medications	No systematic studies in human pregnancy	C
Fluoxetine (Prozac)	Has been studied in human pregnancy, with data from meta-analysis and neurodevelopmental follow-up	More reports of neonatal side effects than some other antidepressants	C
Paroxetine (Paxil)	None	No behavioral studies in human pregnancy	D; ACOG recommends that this drug be avoided in pregnancy, if possible
		More reports of neonatal side effects than most other antidepressants
		Association with right ventricular outflow tract obstruction, anencephaly, craniosynostosis, and omphalocele, but absolute risk is small
Sertraline (Zoloft)	Relatively well studied in human pregnancy	Possible association with omphalocele and septal defects, but absolute risk is small	C
	Fewer neonatal side effects reported
* ACOG reports that neonates exposed to SSRIs late in the third trimester have developed complications such as jitteriness, mild respiratory distress, transient tachypnea, and poor tone.
Pregnancy category C–Animal studies have shown an adverse effect and there are no adequate and well-controlled studies in pregnant women, or no animal studies have been conducted and there are no adequate and well-controlled studies in pregnant women.
Pregnancy category D–Has been found to have a harmful effect on fetuses.
Adapted from “Information for Physicians on Prescription Products to Treat Perinatal Depression,” University of Illinois at Chicago Perinatal Mental Health Project, August 2007 (www.psych.uic.edu/research/perinatalmentalhealth/).

Weigh slight risk of defects against risks associated with discontinuation

These studies confirm that SSRIs are not major teratogens. Nevertheless, any woman planning to conceive and who is worried about using an SSRI during pregnancy should weigh these findings against the risks associated with discontinuing an SSRI during pregnancy.

 

Heightened surveillance may be justified

Consider second-trimester targeted ultrasonography to rule out fetal anomalies in women who take an SSRI in early pregnancy. And consider psychiatric monitoring for women who discontinue an SSRI before conception or in early pregnancy.

A. No. However, these two studies found some evidence that use of selective serotonin-reuptake inhibitors (SSRIs) at the time of conception or during pregnancy is associated with anencephaly, craniosynostosis, and omphalocele—although the absolute risk was very low and the association needs to be confirmed by further study. These studies also found a significant association between specific SSRIs and birth defects, such as paroxetine (Paxil) and right ventricular outflow tract obstruction, but, again, the absolute risk was very low and the birth defects in question are rare.

Expert Commentary

Because depression is fairly common among women of reproductive age and is often treated with SSRIs, the issue of teratogenicity is important. Earlier investigations suggested that use of these drugs—particularly paroxetine—during early pregnancy increases the risk of heart defects. These two ongoing case-control studies help clarify the relationship between prenatal use of SSRIs and birth defects, although the issue still has not been addressed definitively.

Both studies involved large populations

The first study was conducted by investigators from the Centers for Disease Control and Prevention and the University of British Columbia. It involved 9,622 infants with major birth defects and 4,092 control infants, all of whom were born between 1997 and 2002. Case infants were identified using birth-defect surveillance systems in eight US states, and control infants were randomly selected from the same regions. A woman was considered exposed to an SSRI if she used any of the medications from 1 month before to 3 months after conception.

Investigators found no significant association between maternal SSRI use in early pregnancy and most categories of birth defects, including congenital heart defects. However, they found a significant association between maternal SSRI use and anencephaly (odds ratio [OR], 2.4; 95% confidence interval [CI], 1.1–5.1), craniosynostosis (OR, 2.5; 95% CI, 1.5–4.0), and omphalocele (OR, 2.8; 95% CI, 1.3–5.7). Use of paroxetine correlated with higher pooled ORs for these three birth defects, as well as a significantly increased risk of right ventricular outflow tract obstruction.

The study by Louik and associates was funded by the National Institutes of Health and GlaxoSmithKline, the manufacturer of Paxil. It involved 9,849 infants with major birth defects and 5,860 control infants, all of whom were born in the United States or Canada between 1993 and 2005. All infants in the case and control groups were identified through their participation in the Slone Epidemiology Center Birth Defects Study, a continuing analysis of medication use in pregnancy. Because Louik and colleagues focused on first-trimester use of SSRIs, exposure was defined as use of any SSRI from 28 days before the last menstrual period through the fourth lunar month (112 days after the last menstrual period.

Use of SSRIs overall was not associated with heart defects, craniosynostosis, or omphalocele, but a significant association was found between paroxetine use and right ventricular outflow tract obstruction (based on 6 exposed subjects) and between septal defects and sertraline use (based on 13 exposed subjects).

TABLE

SSRIs in pregnancy: How they stack up

ANTIDEPRESSANT	ADVANTAGES	DISADVANTAGES*	PREGNANCY CATEGORY
Citalopram (Celexa)	Few interactions with other medications	No behavioral studies in human pregnancy	C
Escitalopram (Lexapro)	Few interactions with other medications	No systematic studies in human pregnancy	C
Fluoxetine (Prozac)	Has been studied in human pregnancy, with data from meta-analysis and neurodevelopmental follow-up	More reports of neonatal side effects than some other antidepressants	C
Paroxetine (Paxil)	None	No behavioral studies in human pregnancy	D; ACOG recommends that this drug be avoided in pregnancy, if possible
		More reports of neonatal side effects than most other antidepressants
		Association with right ventricular outflow tract obstruction, anencephaly, craniosynostosis, and omphalocele, but absolute risk is small
Sertraline (Zoloft)	Relatively well studied in human pregnancy	Possible association with omphalocele and septal defects, but absolute risk is small	C
	Fewer neonatal side effects reported
* ACOG reports that neonates exposed to SSRIs late in the third trimester have developed complications such as jitteriness, mild respiratory distress, transient tachypnea, and poor tone.
Pregnancy category C–Animal studies have shown an adverse effect and there are no adequate and well-controlled studies in pregnant women, or no animal studies have been conducted and there are no adequate and well-controlled studies in pregnant women.
Pregnancy category D–Has been found to have a harmful effect on fetuses.
Adapted from “Information for Physicians on Prescription Products to Treat Perinatal Depression,” University of Illinois at Chicago Perinatal Mental Health Project, August 2007 (www.psych.uic.edu/research/perinatalmentalhealth/).

Weigh slight risk of defects against risks associated with discontinuation

These studies confirm that SSRIs are not major teratogens. Nevertheless, any woman planning to conceive and who is worried about using an SSRI during pregnancy should weigh these findings against the risks associated with discontinuing an SSRI during pregnancy.

 

Heightened surveillance may be justified

Consider second-trimester targeted ultrasonography to rule out fetal anomalies in women who take an SSRI in early pregnancy. And consider psychiatric monitoring for women who discontinue an SSRI before conception or in early pregnancy.

A. No. However, these two studies found some evidence that use of selective serotonin-reuptake inhibitors (SSRIs) at the time of conception or during pregnancy is associated with anencephaly, craniosynostosis, and omphalocele—although the absolute risk was very low and the association needs to be confirmed by further study. These studies also found a significant association between specific SSRIs and birth defects, such as paroxetine (Paxil) and right ventricular outflow tract obstruction, but, again, the absolute risk was very low and the birth defects in question are rare.

Expert Commentary

Because depression is fairly common among women of reproductive age and is often treated with SSRIs, the issue of teratogenicity is important. Earlier investigations suggested that use of these drugs—particularly paroxetine—during early pregnancy increases the risk of heart defects. These two ongoing case-control studies help clarify the relationship between prenatal use of SSRIs and birth defects, although the issue still has not been addressed definitively.

Both studies involved large populations

The first study was conducted by investigators from the Centers for Disease Control and Prevention and the University of British Columbia. It involved 9,622 infants with major birth defects and 4,092 control infants, all of whom were born between 1997 and 2002. Case infants were identified using birth-defect surveillance systems in eight US states, and control infants were randomly selected from the same regions. A woman was considered exposed to an SSRI if she used any of the medications from 1 month before to 3 months after conception.

Investigators found no significant association between maternal SSRI use in early pregnancy and most categories of birth defects, including congenital heart defects. However, they found a significant association between maternal SSRI use and anencephaly (odds ratio [OR], 2.4; 95% confidence interval [CI], 1.1–5.1), craniosynostosis (OR, 2.5; 95% CI, 1.5–4.0), and omphalocele (OR, 2.8; 95% CI, 1.3–5.7). Use of paroxetine correlated with higher pooled ORs for these three birth defects, as well as a significantly increased risk of right ventricular outflow tract obstruction.

The study by Louik and associates was funded by the National Institutes of Health and GlaxoSmithKline, the manufacturer of Paxil. It involved 9,849 infants with major birth defects and 5,860 control infants, all of whom were born in the United States or Canada between 1993 and 2005. All infants in the case and control groups were identified through their participation in the Slone Epidemiology Center Birth Defects Study, a continuing analysis of medication use in pregnancy. Because Louik and colleagues focused on first-trimester use of SSRIs, exposure was defined as use of any SSRI from 28 days before the last menstrual period through the fourth lunar month (112 days after the last menstrual period.

Use of SSRIs overall was not associated with heart defects, craniosynostosis, or omphalocele, but a significant association was found between paroxetine use and right ventricular outflow tract obstruction (based on 6 exposed subjects) and between septal defects and sertraline use (based on 13 exposed subjects).

TABLE

SSRIs in pregnancy: How they stack up

ANTIDEPRESSANT	ADVANTAGES	DISADVANTAGES*	PREGNANCY CATEGORY
Citalopram (Celexa)	Few interactions with other medications	No behavioral studies in human pregnancy	C
Escitalopram (Lexapro)	Few interactions with other medications	No systematic studies in human pregnancy	C
Fluoxetine (Prozac)	Has been studied in human pregnancy, with data from meta-analysis and neurodevelopmental follow-up	More reports of neonatal side effects than some other antidepressants	C
Paroxetine (Paxil)	None	No behavioral studies in human pregnancy	D; ACOG recommends that this drug be avoided in pregnancy, if possible
		More reports of neonatal side effects than most other antidepressants
		Association with right ventricular outflow tract obstruction, anencephaly, craniosynostosis, and omphalocele, but absolute risk is small
Sertraline (Zoloft)	Relatively well studied in human pregnancy	Possible association with omphalocele and septal defects, but absolute risk is small	C
	Fewer neonatal side effects reported
* ACOG reports that neonates exposed to SSRIs late in the third trimester have developed complications such as jitteriness, mild respiratory distress, transient tachypnea, and poor tone.
Pregnancy category C–Animal studies have shown an adverse effect and there are no adequate and well-controlled studies in pregnant women, or no animal studies have been conducted and there are no adequate and well-controlled studies in pregnant women.
Pregnancy category D–Has been found to have a harmful effect on fetuses.
Adapted from “Information for Physicians on Prescription Products to Treat Perinatal Depression,” University of Illinois at Chicago Perinatal Mental Health Project, August 2007 (www.psych.uic.edu/research/perinatalmentalhealth/).

Weigh slight risk of defects against risks associated with discontinuation

These studies confirm that SSRIs are not major teratogens. Nevertheless, any woman planning to conceive and who is worried about using an SSRI during pregnancy should weigh these findings against the risks associated with discontinuing an SSRI during pregnancy.

 

Heightened surveillance may be justified

Consider second-trimester targeted ultrasonography to rule out fetal anomalies in women who take an SSRI in early pregnancy. And consider psychiatric monitoring for women who discontinue an SSRI before conception or in early pregnancy.

A. Gynecologic symptoms such as abdominal and pelvic swelling, abnormal bleeding, and genital organ pain were most likely to prompt evaluation for ovarian cancer in this review of Surveillance, Epidemiology, and End Results (SEER) and Medicare data for 3,250 women 65 years and older. Gastrointestinal (GI) symptoms such as nausea and vomiting, constipation, diarrhea, and other digestive disorders were associated with diagnosis at a later stage, whereas gynecologic symptoms were associated with earlier disease.

Expert Commentary

A substantial body of research over the past decade has demonstrated that, even in the earliest stages, ovarian cancer produces symptoms. This study by Ryerson and colleagues is a significant contribution to that body of evidence and underscores the importance of including ovarian cancer in the differential diagnosis when a patient reports gynecologic, GI, or abdominal symptoms.

Early recognition is critical

Because we lack an effective screening test for ovarian cancer, early recognition and prompt evaluation of symptoms may be critical to improve prognosis. The cure rate for early-stage disease is 70% to 90%, compared with 10% to 30% for advanced stages.

This study is consistent with other research demonstrating that more than 80% of women with early-stage ovarian cancer have symptoms months before they are given a diagnosis. Compared with women who have GI symptoms, those who have gynecologic symptoms underwent abdominal or pelvic imaging and surgical evaluation sooner after reporting symptoms.

Large database and inclusion of ICD-9 data are strengths of this study

This study utilized population data from 13 geographic regions of the country. More important, it evaluated the ICD-9 diagnosis that prompted a visit to a physician or a procedure before ovarian cancer was diagnosed. Because women were unaware that they would subsequently be given a diagnosis of ovarian cancer, the design eliminates recall bias that has been at issue in earlier studies.

ICD-9 data are also a weakness

The fact that ICD-9 diagnostic data for billing purposes were used as a substitute for patient symptoms is a weakness of this study. Physicians frequently report only one ICD-9 diagnosis per encounter, so this study may significantly underreport the symptoms experienced by women with ovarian cancer.

The fact that this study included only women older than 65 years is another weakness, as is the fact that only 3,250 of 8,357 women were ultimately included in the final analysis—raising concern of selection bias.

Bottom line: Keep symptoms in mind

Both patients and physicians alike should be aware that gynecologic, GI, and urinary symptoms may be indicators of ovarian cancer and may warrant further diagnostic evaluation. Until there is a screening test for ovarian cancer, heightened awareness is best.

A. Gynecologic symptoms such as abdominal and pelvic swelling, abnormal bleeding, and genital organ pain were most likely to prompt evaluation for ovarian cancer in this review of Surveillance, Epidemiology, and End Results (SEER) and Medicare data for 3,250 women 65 years and older. Gastrointestinal (GI) symptoms such as nausea and vomiting, constipation, diarrhea, and other digestive disorders were associated with diagnosis at a later stage, whereas gynecologic symptoms were associated with earlier disease.

Expert Commentary

A substantial body of research over the past decade has demonstrated that, even in the earliest stages, ovarian cancer produces symptoms. This study by Ryerson and colleagues is a significant contribution to that body of evidence and underscores the importance of including ovarian cancer in the differential diagnosis when a patient reports gynecologic, GI, or abdominal symptoms.

Early recognition is critical

Because we lack an effective screening test for ovarian cancer, early recognition and prompt evaluation of symptoms may be critical to improve prognosis. The cure rate for early-stage disease is 70% to 90%, compared with 10% to 30% for advanced stages.

This study is consistent with other research demonstrating that more than 80% of women with early-stage ovarian cancer have symptoms months before they are given a diagnosis. Compared with women who have GI symptoms, those who have gynecologic symptoms underwent abdominal or pelvic imaging and surgical evaluation sooner after reporting symptoms.

Large database and inclusion of ICD-9 data are strengths of this study

This study utilized population data from 13 geographic regions of the country. More important, it evaluated the ICD-9 diagnosis that prompted a visit to a physician or a procedure before ovarian cancer was diagnosed. Because women were unaware that they would subsequently be given a diagnosis of ovarian cancer, the design eliminates recall bias that has been at issue in earlier studies.

ICD-9 data are also a weakness

The fact that ICD-9 diagnostic data for billing purposes were used as a substitute for patient symptoms is a weakness of this study. Physicians frequently report only one ICD-9 diagnosis per encounter, so this study may significantly underreport the symptoms experienced by women with ovarian cancer.

The fact that this study included only women older than 65 years is another weakness, as is the fact that only 3,250 of 8,357 women were ultimately included in the final analysis—raising concern of selection bias.

Bottom line: Keep symptoms in mind

Both patients and physicians alike should be aware that gynecologic, GI, and urinary symptoms may be indicators of ovarian cancer and may warrant further diagnostic evaluation. Until there is a screening test for ovarian cancer, heightened awareness is best.

A. Gynecologic symptoms such as abdominal and pelvic swelling, abnormal bleeding, and genital organ pain were most likely to prompt evaluation for ovarian cancer in this review of Surveillance, Epidemiology, and End Results (SEER) and Medicare data for 3,250 women 65 years and older. Gastrointestinal (GI) symptoms such as nausea and vomiting, constipation, diarrhea, and other digestive disorders were associated with diagnosis at a later stage, whereas gynecologic symptoms were associated with earlier disease.

Expert Commentary

A substantial body of research over the past decade has demonstrated that, even in the earliest stages, ovarian cancer produces symptoms. This study by Ryerson and colleagues is a significant contribution to that body of evidence and underscores the importance of including ovarian cancer in the differential diagnosis when a patient reports gynecologic, GI, or abdominal symptoms.

Early recognition is critical

Because we lack an effective screening test for ovarian cancer, early recognition and prompt evaluation of symptoms may be critical to improve prognosis. The cure rate for early-stage disease is 70% to 90%, compared with 10% to 30% for advanced stages.

This study is consistent with other research demonstrating that more than 80% of women with early-stage ovarian cancer have symptoms months before they are given a diagnosis. Compared with women who have GI symptoms, those who have gynecologic symptoms underwent abdominal or pelvic imaging and surgical evaluation sooner after reporting symptoms.

Large database and inclusion of ICD-9 data are strengths of this study

This study utilized population data from 13 geographic regions of the country. More important, it evaluated the ICD-9 diagnosis that prompted a visit to a physician or a procedure before ovarian cancer was diagnosed. Because women were unaware that they would subsequently be given a diagnosis of ovarian cancer, the design eliminates recall bias that has been at issue in earlier studies.

ICD-9 data are also a weakness

The fact that ICD-9 diagnostic data for billing purposes were used as a substitute for patient symptoms is a weakness of this study. Physicians frequently report only one ICD-9 diagnosis per encounter, so this study may significantly underreport the symptoms experienced by women with ovarian cancer.

The fact that this study included only women older than 65 years is another weakness, as is the fact that only 3,250 of 8,357 women were ultimately included in the final analysis—raising concern of selection bias.

Bottom line: Keep symptoms in mind

Both patients and physicians alike should be aware that gynecologic, GI, and urinary symptoms may be indicators of ovarian cancer and may warrant further diagnostic evaluation. Until there is a screening test for ovarian cancer, heightened awareness is best.

Patients who want to be sexually active but suffer iatrogenic vaginal constriction or shortening, or both, are a surgical challenge. Their condition may require any of a variety of nonsurgical and surgical procedures to restore the ability to have gratifying sexual intercourse, and they may need considerable preoperative and postoperative counseling and management.

What is the basis of this problem?

The cause of vaginal shortening or constriction is most often surgical. Rarely is systemic disease or a localized condition, such as urogenital atrophy, responsible.

Prolapse procedures. Most procedures that result in vaginal shortening or constriction are ones performed to correct pelvic organ prolapse (POP), notably:

• posterior colpoperineorrhaphy with levatorplasty
  
• hysterectomy, whether abdominal or vaginal, during which too much of the upper vagina is taken with the cervix
  
• anterior and posterior colporrhaphy in which vaginal plication and trimming are performed overzealously.
  

Surgical mesh. More recently, as a variety of mesh materials are used to augment repair of prolapse, mesh sometimes needs to be removed because of erosion, extrusion, infection, or pain. Under such circumstances, closing or covering raw surfaces without creating vaginal constriction or shortening is at times a challenge.

Radiation therapy to the pelvis can result in vaginal shortening, constriction, and obliteration.

How do you avoid creating these problems?

Techniques to avoid vaginal shortening and constriction during vaginal reconstructive surgery include appropriate use of levatorplasty during posterior colpoperineorrhaphy. Although levatorplasty is, at times, the only way to decrease the size of a large vaginal hiatus, it should be used only in the distal third of the vagina. Levatorplasty above this area often creates vaginal constriction that results in postoperative dyspareunia.

Also, avoid 1) overzealous trimming during anterior and posterior colporrhaphy and 2) removing too much vagina at vaginal or abdominal hysterectomy.

Last, it is important that a patient who has undergone vaginal reconstructive surgery have a vaginal exam within 2 weeks after surgery. This will ensure that the vaginal incisions do not fuse, thus creating vaginal scarring, closure, and constriction.

How is correction approached?

Various modifications of a McIndoe procedure have been described for vaginal agenesis, but surgical correction of iatrogenic vaginal shortening or constriction is not well described; few case series exist in the literature. Consensus is lacking on what the minimal length of a vagina must be to preserve normal sexual function, and no standard exists in regards to either normal vaginal caliber or the relationship of the perineum and perineal body to the distal posterior vagina.

That being said, we have recognized the following correlates of a successful return to sexual function after surgery for vaginal constriction or shortening:

• The vagina should, at minimum, be 7 cm long to have the potential for normal function
  
• The vaginal opening should easily admit two fingers during examination
  
• The relationship of the posterior vagina and the perineum should be a perpendicular one, in which a built-up perineum attaches to the posterior vagina at the posterior fourchette at a 90° angle
  
• There should be no buildup of perineal skin above and beyond the posterior fourchette.
  

Is surgery the first intervention?

No. The patient should first undergo an attempt at nonsurgical management. This usually involves:

• vaginal estrogen cream in a postmenopausal patient
  
• appropriate utilization of a vaginal dilator.
  

For a dilator to be successful, it must be able to be advanced through a vaginal constriction. Dilation will, most likely, be unsuccessful if the dilator reaches but does not pass through the constriction. Furthermore, dilation of a shortened vagina is rarely successful unless you are able to use a bicycle seat-type dilator. In this situation, you must, first, have patience and, second, apply a significant amount of vaginal estrogen cream in the hope of elongating the vagina.

What are options for surgery?

If nonsurgical management of vaginal constriction or shortening is unsuccessful or unsatisfactory, next choose an operation based on the needs of the individual patient. Some procedures involve placement of a skin graft or, possibly, other biologic material in the vagina to close over defects after constriction has been taken down or the vagina has been appropriately opened up. (It is fortunate that the vagina heals well by secondary intention; often, simply taking down the constriction and allowing the vagina to heal by secondary intention is successful.)

 

How is constriction released?

It is important to cut through the constriction and completely separate the tissue during the takedown of vaginal constriction. At this point, you need to decide whether to allow the separated vagina to heal by secondary intention or to cover the defect with a skin graft or other biologic material.

Whichever course you choose, keep the vagina open during the immediate postoperative period. Doing so may require placement of a vaginal stent, numerous postoperative exams, use of a vaginal dilator, or a combination of these measures.

When constriction rings are present in the face of ample vaginal length, you can perform a Z-plasty, in which the lines of a letter Z are incised transversely or longitudinally across the constricted region and the two flaps that have been created from the Z are transposed. This maneuver releases constriction well.

When constriction extends distally, the procedure used is, basically, a reverse perineoplasty: Cut the constriction band longitudinally, undermine the vagina, and then sew it back transversely. This relieves the distal band.

In a severe case of vaginal constriction, thigh flaps that are left on their vascular pedicle can be brought into the vagina to fill the gap created by cutting through the constriction. Initial incisions are made laterally in the vagina (unilaterally or bilaterally, depending on the degree of constriction) and extended to the perineum/vulva. Measurements are made to determine the length and width of flap(s) needed. The flaps are then mobilized, rotated into the defect(s), and sutured into place. This technique significantly increases the diameter of the vagina and can add length, if needed.

What about correcting shortening?

An iatrogenically shortened vagina presents the most challenging of cases. The vagina must be opened up at the cuff; ideally, this produces adequate length without having to enter the peritoneum.

Patients who want to be sexually active but suffer iatrogenic vaginal constriction or shortening, or both, are a surgical challenge. Their condition may require any of a variety of nonsurgical and surgical procedures to restore the ability to have gratifying sexual intercourse, and they may need considerable preoperative and postoperative counseling and management.

What is the basis of this problem?

The cause of vaginal shortening or constriction is most often surgical. Rarely is systemic disease or a localized condition, such as urogenital atrophy, responsible.

Prolapse procedures. Most procedures that result in vaginal shortening or constriction are ones performed to correct pelvic organ prolapse (POP), notably:

• posterior colpoperineorrhaphy with levatorplasty
  
• hysterectomy, whether abdominal or vaginal, during which too much of the upper vagina is taken with the cervix
  
• anterior and posterior colporrhaphy in which vaginal plication and trimming are performed overzealously.
  

Surgical mesh. More recently, as a variety of mesh materials are used to augment repair of prolapse, mesh sometimes needs to be removed because of erosion, extrusion, infection, or pain. Under such circumstances, closing or covering raw surfaces without creating vaginal constriction or shortening is at times a challenge.

Radiation therapy to the pelvis can result in vaginal shortening, constriction, and obliteration.

How do you avoid creating these problems?

Techniques to avoid vaginal shortening and constriction during vaginal reconstructive surgery include appropriate use of levatorplasty during posterior colpoperineorrhaphy. Although levatorplasty is, at times, the only way to decrease the size of a large vaginal hiatus, it should be used only in the distal third of the vagina. Levatorplasty above this area often creates vaginal constriction that results in postoperative dyspareunia.

Also, avoid 1) overzealous trimming during anterior and posterior colporrhaphy and 2) removing too much vagina at vaginal or abdominal hysterectomy.

Last, it is important that a patient who has undergone vaginal reconstructive surgery have a vaginal exam within 2 weeks after surgery. This will ensure that the vaginal incisions do not fuse, thus creating vaginal scarring, closure, and constriction.

How is correction approached?

Various modifications of a McIndoe procedure have been described for vaginal agenesis, but surgical correction of iatrogenic vaginal shortening or constriction is not well described; few case series exist in the literature. Consensus is lacking on what the minimal length of a vagina must be to preserve normal sexual function, and no standard exists in regards to either normal vaginal caliber or the relationship of the perineum and perineal body to the distal posterior vagina.

That being said, we have recognized the following correlates of a successful return to sexual function after surgery for vaginal constriction or shortening:

• The vagina should, at minimum, be 7 cm long to have the potential for normal function
  
• The vaginal opening should easily admit two fingers during examination
  
• The relationship of the posterior vagina and the perineum should be a perpendicular one, in which a built-up perineum attaches to the posterior vagina at the posterior fourchette at a 90° angle
  
• There should be no buildup of perineal skin above and beyond the posterior fourchette.
  

Is surgery the first intervention?

No. The patient should first undergo an attempt at nonsurgical management. This usually involves:

• vaginal estrogen cream in a postmenopausal patient
  
• appropriate utilization of a vaginal dilator.
  

For a dilator to be successful, it must be able to be advanced through a vaginal constriction. Dilation will, most likely, be unsuccessful if the dilator reaches but does not pass through the constriction. Furthermore, dilation of a shortened vagina is rarely successful unless you are able to use a bicycle seat-type dilator. In this situation, you must, first, have patience and, second, apply a significant amount of vaginal estrogen cream in the hope of elongating the vagina.

What are options for surgery?

If nonsurgical management of vaginal constriction or shortening is unsuccessful or unsatisfactory, next choose an operation based on the needs of the individual patient. Some procedures involve placement of a skin graft or, possibly, other biologic material in the vagina to close over defects after constriction has been taken down or the vagina has been appropriately opened up. (It is fortunate that the vagina heals well by secondary intention; often, simply taking down the constriction and allowing the vagina to heal by secondary intention is successful.)

 

How is constriction released?

It is important to cut through the constriction and completely separate the tissue during the takedown of vaginal constriction. At this point, you need to decide whether to allow the separated vagina to heal by secondary intention or to cover the defect with a skin graft or other biologic material.

Whichever course you choose, keep the vagina open during the immediate postoperative period. Doing so may require placement of a vaginal stent, numerous postoperative exams, use of a vaginal dilator, or a combination of these measures.

When constriction rings are present in the face of ample vaginal length, you can perform a Z-plasty, in which the lines of a letter Z are incised transversely or longitudinally across the constricted region and the two flaps that have been created from the Z are transposed. This maneuver releases constriction well.

When constriction extends distally, the procedure used is, basically, a reverse perineoplasty: Cut the constriction band longitudinally, undermine the vagina, and then sew it back transversely. This relieves the distal band.

In a severe case of vaginal constriction, thigh flaps that are left on their vascular pedicle can be brought into the vagina to fill the gap created by cutting through the constriction. Initial incisions are made laterally in the vagina (unilaterally or bilaterally, depending on the degree of constriction) and extended to the perineum/vulva. Measurements are made to determine the length and width of flap(s) needed. The flaps are then mobilized, rotated into the defect(s), and sutured into place. This technique significantly increases the diameter of the vagina and can add length, if needed.

What about correcting shortening?

An iatrogenically shortened vagina presents the most challenging of cases. The vagina must be opened up at the cuff; ideally, this produces adequate length without having to enter the peritoneum.

Patients who want to be sexually active but suffer iatrogenic vaginal constriction or shortening, or both, are a surgical challenge. Their condition may require any of a variety of nonsurgical and surgical procedures to restore the ability to have gratifying sexual intercourse, and they may need considerable preoperative and postoperative counseling and management.

What is the basis of this problem?

The cause of vaginal shortening or constriction is most often surgical. Rarely is systemic disease or a localized condition, such as urogenital atrophy, responsible.

Prolapse procedures. Most procedures that result in vaginal shortening or constriction are ones performed to correct pelvic organ prolapse (POP), notably:

• posterior colpoperineorrhaphy with levatorplasty
  
• hysterectomy, whether abdominal or vaginal, during which too much of the upper vagina is taken with the cervix
  
• anterior and posterior colporrhaphy in which vaginal plication and trimming are performed overzealously.
  

Surgical mesh. More recently, as a variety of mesh materials are used to augment repair of prolapse, mesh sometimes needs to be removed because of erosion, extrusion, infection, or pain. Under such circumstances, closing or covering raw surfaces without creating vaginal constriction or shortening is at times a challenge.

Radiation therapy to the pelvis can result in vaginal shortening, constriction, and obliteration.

How do you avoid creating these problems?

Techniques to avoid vaginal shortening and constriction during vaginal reconstructive surgery include appropriate use of levatorplasty during posterior colpoperineorrhaphy. Although levatorplasty is, at times, the only way to decrease the size of a large vaginal hiatus, it should be used only in the distal third of the vagina. Levatorplasty above this area often creates vaginal constriction that results in postoperative dyspareunia.

Also, avoid 1) overzealous trimming during anterior and posterior colporrhaphy and 2) removing too much vagina at vaginal or abdominal hysterectomy.

Last, it is important that a patient who has undergone vaginal reconstructive surgery have a vaginal exam within 2 weeks after surgery. This will ensure that the vaginal incisions do not fuse, thus creating vaginal scarring, closure, and constriction.

How is correction approached?

Various modifications of a McIndoe procedure have been described for vaginal agenesis, but surgical correction of iatrogenic vaginal shortening or constriction is not well described; few case series exist in the literature. Consensus is lacking on what the minimal length of a vagina must be to preserve normal sexual function, and no standard exists in regards to either normal vaginal caliber or the relationship of the perineum and perineal body to the distal posterior vagina.

That being said, we have recognized the following correlates of a successful return to sexual function after surgery for vaginal constriction or shortening:

• The vagina should, at minimum, be 7 cm long to have the potential for normal function
  
• The vaginal opening should easily admit two fingers during examination
  
• The relationship of the posterior vagina and the perineum should be a perpendicular one, in which a built-up perineum attaches to the posterior vagina at the posterior fourchette at a 90° angle
  
• There should be no buildup of perineal skin above and beyond the posterior fourchette.
  

Is surgery the first intervention?

No. The patient should first undergo an attempt at nonsurgical management. This usually involves:

• vaginal estrogen cream in a postmenopausal patient
  
• appropriate utilization of a vaginal dilator.
  

For a dilator to be successful, it must be able to be advanced through a vaginal constriction. Dilation will, most likely, be unsuccessful if the dilator reaches but does not pass through the constriction. Furthermore, dilation of a shortened vagina is rarely successful unless you are able to use a bicycle seat-type dilator. In this situation, you must, first, have patience and, second, apply a significant amount of vaginal estrogen cream in the hope of elongating the vagina.

What are options for surgery?

If nonsurgical management of vaginal constriction or shortening is unsuccessful or unsatisfactory, next choose an operation based on the needs of the individual patient. Some procedures involve placement of a skin graft or, possibly, other biologic material in the vagina to close over defects after constriction has been taken down or the vagina has been appropriately opened up. (It is fortunate that the vagina heals well by secondary intention; often, simply taking down the constriction and allowing the vagina to heal by secondary intention is successful.)

 

How is constriction released?

It is important to cut through the constriction and completely separate the tissue during the takedown of vaginal constriction. At this point, you need to decide whether to allow the separated vagina to heal by secondary intention or to cover the defect with a skin graft or other biologic material.

Whichever course you choose, keep the vagina open during the immediate postoperative period. Doing so may require placement of a vaginal stent, numerous postoperative exams, use of a vaginal dilator, or a combination of these measures.

When constriction rings are present in the face of ample vaginal length, you can perform a Z-plasty, in which the lines of a letter Z are incised transversely or longitudinally across the constricted region and the two flaps that have been created from the Z are transposed. This maneuver releases constriction well.

When constriction extends distally, the procedure used is, basically, a reverse perineoplasty: Cut the constriction band longitudinally, undermine the vagina, and then sew it back transversely. This relieves the distal band.

In a severe case of vaginal constriction, thigh flaps that are left on their vascular pedicle can be brought into the vagina to fill the gap created by cutting through the constriction. Initial incisions are made laterally in the vagina (unilaterally or bilaterally, depending on the degree of constriction) and extended to the perineum/vulva. Measurements are made to determine the length and width of flap(s) needed. The flaps are then mobilized, rotated into the defect(s), and sutured into place. This technique significantly increases the diameter of the vagina and can add length, if needed.

What about correcting shortening?

An iatrogenically shortened vagina presents the most challenging of cases. The vagina must be opened up at the cuff; ideally, this produces adequate length without having to enter the peritoneum.

A.Maybe. In this secondary analysis of Women’s Health Initiative (WHI) data, women who began HRT nearer to time of menopause had a lower risk of coronary heart disease (CHD) than did women who began HRT more distant from menopause, and whose risk was elevated. The trend was not statistically significant, however. On the other hand, the risk of stroke was significantly elevated for all women—regardless of when HRT was begun.

Expert Commentary

The putative protective effects of HRT on the risk of cardiovascular disease (CVD) suggested by observational studies for many years¹ were completely negated by prospective, randomized trials.^2,3 The WHI clinical trials reported no benefits with unopposed estrogen and a statistically significant greater risk of CVD events with combination HRT (odds ratio [OR], 1.24; 95% confidence interval [CI], 1.00–1.54).

The divergent results between observational studies and clinical trials have been attributed to several potential confounding factors, including methodologic differences such as healthy-use bias, compliance bias, and incomplete capture of early clinical events, or biological differences such as formulation and dose of the hormone regimen, time since menopause, and stage of atherosclerosis.⁴

Interestingly, observational studies of HRT in menopausal women have been remarkably consistent with randomized studies in predicting other risks, such as stroke, breast cancer, and thromboembolic events, as well as the benefits associated with HRT in regard to osteoporosis-related fractures and colon cancer. There is apparently something unique about CHD that accounts for divergent results between observational and controlled studies.

Earlier data suggested HRT is better suited to younger women

Rossouw and colleagues address 2 confounding factors—years since menopause and age of subjects when they started HRT—to explore the possibility that HRT may protect against CVD in younger, healthier women and be hazardous in older women who have preexisting cardiovascular disease. Support for this hypothesis comes from several sources, including animal studies and controlled and observational studies in postmenopausal women.

For example, in observational studies such as the Nurses Health Study, which consistently reported HRT-related protective effects on CVD, the postmenopausal women were younger (between 30 and 55 years old) and leaner (mean body mass index [BMI], 24.3) and had begun using hormones within 2 years after menopause.⁵ They were, overall, quite different from the menopausal women in the WHI, who were older (mean age, 63 years) and heavier (mean BMI of 28.5) and who had been menopausal for about 10 years at the time of enrollment, when they started using HRT.²

Findings confirm greater hazard for women well past menopause

Rossouw and colleagues conducted secondary analyses of data from the 2 WHI randomized trials, looking at the effect of HRT on CHD and stroke across categories of age and years since menopause. They found that:

• Among younger women with less than 10 years since menopause, the hazard ratio (HR) for CHD was 0.76 (CI, 0.50–1.16), compared with 1.10 (CI, 0.84–1.45) and 1.28 (CI, 1.03–1.58) for the older groups with, respectively, 10 to 19 and more than 20 years after menopause
  
• The effects of HRT on total mortality tended to be more favorable in younger women than in older women (P for trend, .06)
  
• The presence of vasomotor symptoms at baseline had a significant impact on the increased risk of CHD with HRT in women age 70 to 79 years or in women with 20 or more years since menopause—but not in the younger group
  
• HRT increased the risk of stroke by 32%, regardless of age and years since menopause.
  

In younger women, hormones are a reasonable, short-term option

These secondary analyses of WHI data help us understand the divergent results between observational and controlled studies on the effects of HRT on CHD risk in postmenopausal women, and confirm the hypothesis that the health consequences of HRT may vary by distance from menopause, being absent in women close to menopause but significantly high in women distant from menopause, especially if they have vasomotor symptoms.

These data offer some reassurance that, in younger women, hormones remain a reasonable option for short-term treatment of menopausal symptoms but do not necessarily imply an absence of harm, especially over prolonged use.

Limitations of the trial

Although Rossouw and colleagues explore 2 important confounding variables, they did not address others, such as characteristics of study populations (such as estrogen levels) or different hormone regimens, which may be equally, if not more, important in determining the risk–benefit ratio of HRT in menopausal women. It is possible that women who have a lower BMI and who have a lower level of endogenous estrogen may constitute a group that benefits uniquely from hormone use, as a large cohort study of 290,827 postmenopausal women has suggested.⁶

 

It also may be that a different progestin may further reduce the CHD risk by inducing a better lipid profile, reducing plaque formation, and diminishing coronary artery reactivity and blood flow.

Clinical recommendation

These new data do not alter the current recommendation that HRT be used for the relief of disturbing vasomotor symptoms at the lowest effective dose and for the shortest tolerable time.⁷

However, we still have much to learn about the use of hormones in postmenopausal women, and need additional studies designed to allow us to develop the hormone regimen with the best safety and efficacy profile, which should be applied to the subgroups of postmenopausal women that will derive the most benefit.

A.Maybe. In this secondary analysis of Women’s Health Initiative (WHI) data, women who began HRT nearer to time of menopause had a lower risk of coronary heart disease (CHD) than did women who began HRT more distant from menopause, and whose risk was elevated. The trend was not statistically significant, however. On the other hand, the risk of stroke was significantly elevated for all women—regardless of when HRT was begun.

Expert Commentary

The putative protective effects of HRT on the risk of cardiovascular disease (CVD) suggested by observational studies for many years¹ were completely negated by prospective, randomized trials.^2,3 The WHI clinical trials reported no benefits with unopposed estrogen and a statistically significant greater risk of CVD events with combination HRT (odds ratio [OR], 1.24; 95% confidence interval [CI], 1.00–1.54).

The divergent results between observational studies and clinical trials have been attributed to several potential confounding factors, including methodologic differences such as healthy-use bias, compliance bias, and incomplete capture of early clinical events, or biological differences such as formulation and dose of the hormone regimen, time since menopause, and stage of atherosclerosis.⁴

Interestingly, observational studies of HRT in menopausal women have been remarkably consistent with randomized studies in predicting other risks, such as stroke, breast cancer, and thromboembolic events, as well as the benefits associated with HRT in regard to osteoporosis-related fractures and colon cancer. There is apparently something unique about CHD that accounts for divergent results between observational and controlled studies.

Earlier data suggested HRT is better suited to younger women

Rossouw and colleagues address 2 confounding factors—years since menopause and age of subjects when they started HRT—to explore the possibility that HRT may protect against CVD in younger, healthier women and be hazardous in older women who have preexisting cardiovascular disease. Support for this hypothesis comes from several sources, including animal studies and controlled and observational studies in postmenopausal women.

For example, in observational studies such as the Nurses Health Study, which consistently reported HRT-related protective effects on CVD, the postmenopausal women were younger (between 30 and 55 years old) and leaner (mean body mass index [BMI], 24.3) and had begun using hormones within 2 years after menopause.⁵ They were, overall, quite different from the menopausal women in the WHI, who were older (mean age, 63 years) and heavier (mean BMI of 28.5) and who had been menopausal for about 10 years at the time of enrollment, when they started using HRT.²

Findings confirm greater hazard for women well past menopause

Rossouw and colleagues conducted secondary analyses of data from the 2 WHI randomized trials, looking at the effect of HRT on CHD and stroke across categories of age and years since menopause. They found that:

• Among younger women with less than 10 years since menopause, the hazard ratio (HR) for CHD was 0.76 (CI, 0.50–1.16), compared with 1.10 (CI, 0.84–1.45) and 1.28 (CI, 1.03–1.58) for the older groups with, respectively, 10 to 19 and more than 20 years after menopause
  
• The effects of HRT on total mortality tended to be more favorable in younger women than in older women (P for trend, .06)
  
• The presence of vasomotor symptoms at baseline had a significant impact on the increased risk of CHD with HRT in women age 70 to 79 years or in women with 20 or more years since menopause—but not in the younger group
  
• HRT increased the risk of stroke by 32%, regardless of age and years since menopause.
  

In younger women, hormones are a reasonable, short-term option

These secondary analyses of WHI data help us understand the divergent results between observational and controlled studies on the effects of HRT on CHD risk in postmenopausal women, and confirm the hypothesis that the health consequences of HRT may vary by distance from menopause, being absent in women close to menopause but significantly high in women distant from menopause, especially if they have vasomotor symptoms.

These data offer some reassurance that, in younger women, hormones remain a reasonable option for short-term treatment of menopausal symptoms but do not necessarily imply an absence of harm, especially over prolonged use.

Limitations of the trial

Although Rossouw and colleagues explore 2 important confounding variables, they did not address others, such as characteristics of study populations (such as estrogen levels) or different hormone regimens, which may be equally, if not more, important in determining the risk–benefit ratio of HRT in menopausal women. It is possible that women who have a lower BMI and who have a lower level of endogenous estrogen may constitute a group that benefits uniquely from hormone use, as a large cohort study of 290,827 postmenopausal women has suggested.⁶

 

It also may be that a different progestin may further reduce the CHD risk by inducing a better lipid profile, reducing plaque formation, and diminishing coronary artery reactivity and blood flow.

Clinical recommendation

These new data do not alter the current recommendation that HRT be used for the relief of disturbing vasomotor symptoms at the lowest effective dose and for the shortest tolerable time.⁷

However, we still have much to learn about the use of hormones in postmenopausal women, and need additional studies designed to allow us to develop the hormone regimen with the best safety and efficacy profile, which should be applied to the subgroups of postmenopausal women that will derive the most benefit.

A.Maybe. In this secondary analysis of Women’s Health Initiative (WHI) data, women who began HRT nearer to time of menopause had a lower risk of coronary heart disease (CHD) than did women who began HRT more distant from menopause, and whose risk was elevated. The trend was not statistically significant, however. On the other hand, the risk of stroke was significantly elevated for all women—regardless of when HRT was begun.

Expert Commentary

The putative protective effects of HRT on the risk of cardiovascular disease (CVD) suggested by observational studies for many years¹ were completely negated by prospective, randomized trials.^2,3 The WHI clinical trials reported no benefits with unopposed estrogen and a statistically significant greater risk of CVD events with combination HRT (odds ratio [OR], 1.24; 95% confidence interval [CI], 1.00–1.54).

The divergent results between observational studies and clinical trials have been attributed to several potential confounding factors, including methodologic differences such as healthy-use bias, compliance bias, and incomplete capture of early clinical events, or biological differences such as formulation and dose of the hormone regimen, time since menopause, and stage of atherosclerosis.⁴

Interestingly, observational studies of HRT in menopausal women have been remarkably consistent with randomized studies in predicting other risks, such as stroke, breast cancer, and thromboembolic events, as well as the benefits associated with HRT in regard to osteoporosis-related fractures and colon cancer. There is apparently something unique about CHD that accounts for divergent results between observational and controlled studies.

Earlier data suggested HRT is better suited to younger women

Rossouw and colleagues address 2 confounding factors—years since menopause and age of subjects when they started HRT—to explore the possibility that HRT may protect against CVD in younger, healthier women and be hazardous in older women who have preexisting cardiovascular disease. Support for this hypothesis comes from several sources, including animal studies and controlled and observational studies in postmenopausal women.

For example, in observational studies such as the Nurses Health Study, which consistently reported HRT-related protective effects on CVD, the postmenopausal women were younger (between 30 and 55 years old) and leaner (mean body mass index [BMI], 24.3) and had begun using hormones within 2 years after menopause.⁵ They were, overall, quite different from the menopausal women in the WHI, who were older (mean age, 63 years) and heavier (mean BMI of 28.5) and who had been menopausal for about 10 years at the time of enrollment, when they started using HRT.²

Findings confirm greater hazard for women well past menopause

Rossouw and colleagues conducted secondary analyses of data from the 2 WHI randomized trials, looking at the effect of HRT on CHD and stroke across categories of age and years since menopause. They found that:

• Among younger women with less than 10 years since menopause, the hazard ratio (HR) for CHD was 0.76 (CI, 0.50–1.16), compared with 1.10 (CI, 0.84–1.45) and 1.28 (CI, 1.03–1.58) for the older groups with, respectively, 10 to 19 and more than 20 years after menopause
  
• The effects of HRT on total mortality tended to be more favorable in younger women than in older women (P for trend, .06)
  
• The presence of vasomotor symptoms at baseline had a significant impact on the increased risk of CHD with HRT in women age 70 to 79 years or in women with 20 or more years since menopause—but not in the younger group
  
• HRT increased the risk of stroke by 32%, regardless of age and years since menopause.
  

In younger women, hormones are a reasonable, short-term option

These secondary analyses of WHI data help us understand the divergent results between observational and controlled studies on the effects of HRT on CHD risk in postmenopausal women, and confirm the hypothesis that the health consequences of HRT may vary by distance from menopause, being absent in women close to menopause but significantly high in women distant from menopause, especially if they have vasomotor symptoms.

These data offer some reassurance that, in younger women, hormones remain a reasonable option for short-term treatment of menopausal symptoms but do not necessarily imply an absence of harm, especially over prolonged use.

Limitations of the trial

Although Rossouw and colleagues explore 2 important confounding variables, they did not address others, such as characteristics of study populations (such as estrogen levels) or different hormone regimens, which may be equally, if not more, important in determining the risk–benefit ratio of HRT in menopausal women. It is possible that women who have a lower BMI and who have a lower level of endogenous estrogen may constitute a group that benefits uniquely from hormone use, as a large cohort study of 290,827 postmenopausal women has suggested.⁶

 

It also may be that a different progestin may further reduce the CHD risk by inducing a better lipid profile, reducing plaque formation, and diminishing coronary artery reactivity and blood flow.

Clinical recommendation

These new data do not alter the current recommendation that HRT be used for the relief of disturbing vasomotor symptoms at the lowest effective dose and for the shortest tolerable time.⁷

However, we still have much to learn about the use of hormones in postmenopausal women, and need additional studies designed to allow us to develop the hormone regimen with the best safety and efficacy profile, which should be applied to the subgroups of postmenopausal women that will derive the most benefit.

A.Maybe. Current users of hormone replacement therapy (HRT) were significantly more likely to develop ovarian cancer, and to die from it, than never users were. Specifically, 5 or more years of current HRT use resulted in 1 additional case of incident ovarian cancer for every 2,500 users and 1 additional death from ovarian cancer for every 3,300 users. Past HRT users had no elevation in risk.

Expert Commentary

Although rare, ovarian cancer usually is diagnosed late; for this reason, it is the most lethal gynecologic cancer in the US. In the Million Women Study, a massive cohort study carried out in the United Kingdom, roughly 950,000 postmenopausal women were surveyed between 1996 and 2001 and approximately 3 years later. Participants had no history of bilateral oophorectomy or ovarian cancer upon entry into the trial. Of these women, 50% had never used HRT, 30% were current users, and 20% had used it in the past. Over the course of the trial, 2,273 ovarian cancers were diagnosed, and 1,593 women died from the disease.

Elevated risk after 5 years of use

Compared with never users, women who had currently used HRT for longer than 5 years had a higher risk of 1) being given a diagnosis of (relative risk [RR], 1.20; 95% confidence interval [CI], 1.09–1.32) and 2) dying from (RR, 1.23; 95% CI, 1.09–1.38) ovarian cancer. However, current users with less than 5 years of use had no significantly elevated risk.

Other studies have suggested an association between HRT and ovarian cancer, but most have lacked power to determine the incidence of this rare malignancy. Although both estrogen-only and combination HRT were associated with ovarian cancer in current users in this trial, the findings are otherwise similar to those in regard to HRT and incident breast cancer.¹ In the WHI, there was no elevated risk of breast cancer when a woman used combination HRT for less than 5 years.²

Some will choose to counsel women about possible elevated risk

Because the Million Women Study is an observational study, with HRT exposure reported by participants, selection bias is possible (ie, respondents with ovarian cancer may be more likely to report HRT use). With this caveat, some clinicians may choose to counsel women that more than 5 years of unopposed estrogen or combination HRT may increase the risk of ovarian cancer, just as combination HRT raises the risk of breast cancer. A shorter duration of HRT does not appear to increase the risk of ovarian cancer and will probably serve the needs of many symptomatic, newly menopausal women.

A.Maybe. Current users of hormone replacement therapy (HRT) were significantly more likely to develop ovarian cancer, and to die from it, than never users were. Specifically, 5 or more years of current HRT use resulted in 1 additional case of incident ovarian cancer for every 2,500 users and 1 additional death from ovarian cancer for every 3,300 users. Past HRT users had no elevation in risk.

Expert Commentary

Although rare, ovarian cancer usually is diagnosed late; for this reason, it is the most lethal gynecologic cancer in the US. In the Million Women Study, a massive cohort study carried out in the United Kingdom, roughly 950,000 postmenopausal women were surveyed between 1996 and 2001 and approximately 3 years later. Participants had no history of bilateral oophorectomy or ovarian cancer upon entry into the trial. Of these women, 50% had never used HRT, 30% were current users, and 20% had used it in the past. Over the course of the trial, 2,273 ovarian cancers were diagnosed, and 1,593 women died from the disease.

Elevated risk after 5 years of use

Compared with never users, women who had currently used HRT for longer than 5 years had a higher risk of 1) being given a diagnosis of (relative risk [RR], 1.20; 95% confidence interval [CI], 1.09–1.32) and 2) dying from (RR, 1.23; 95% CI, 1.09–1.38) ovarian cancer. However, current users with less than 5 years of use had no significantly elevated risk.

Other studies have suggested an association between HRT and ovarian cancer, but most have lacked power to determine the incidence of this rare malignancy. Although both estrogen-only and combination HRT were associated with ovarian cancer in current users in this trial, the findings are otherwise similar to those in regard to HRT and incident breast cancer.¹ In the WHI, there was no elevated risk of breast cancer when a woman used combination HRT for less than 5 years.²

Some will choose to counsel women about possible elevated risk

Because the Million Women Study is an observational study, with HRT exposure reported by participants, selection bias is possible (ie, respondents with ovarian cancer may be more likely to report HRT use). With this caveat, some clinicians may choose to counsel women that more than 5 years of unopposed estrogen or combination HRT may increase the risk of ovarian cancer, just as combination HRT raises the risk of breast cancer. A shorter duration of HRT does not appear to increase the risk of ovarian cancer and will probably serve the needs of many symptomatic, newly menopausal women.

A.Maybe. Current users of hormone replacement therapy (HRT) were significantly more likely to develop ovarian cancer, and to die from it, than never users were. Specifically, 5 or more years of current HRT use resulted in 1 additional case of incident ovarian cancer for every 2,500 users and 1 additional death from ovarian cancer for every 3,300 users. Past HRT users had no elevation in risk.

Expert Commentary

Although rare, ovarian cancer usually is diagnosed late; for this reason, it is the most lethal gynecologic cancer in the US. In the Million Women Study, a massive cohort study carried out in the United Kingdom, roughly 950,000 postmenopausal women were surveyed between 1996 and 2001 and approximately 3 years later. Participants had no history of bilateral oophorectomy or ovarian cancer upon entry into the trial. Of these women, 50% had never used HRT, 30% were current users, and 20% had used it in the past. Over the course of the trial, 2,273 ovarian cancers were diagnosed, and 1,593 women died from the disease.

Elevated risk after 5 years of use

Compared with never users, women who had currently used HRT for longer than 5 years had a higher risk of 1) being given a diagnosis of (relative risk [RR], 1.20; 95% confidence interval [CI], 1.09–1.32) and 2) dying from (RR, 1.23; 95% CI, 1.09–1.38) ovarian cancer. However, current users with less than 5 years of use had no significantly elevated risk.

Other studies have suggested an association between HRT and ovarian cancer, but most have lacked power to determine the incidence of this rare malignancy. Although both estrogen-only and combination HRT were associated with ovarian cancer in current users in this trial, the findings are otherwise similar to those in regard to HRT and incident breast cancer.¹ In the WHI, there was no elevated risk of breast cancer when a woman used combination HRT for less than 5 years.²

Some will choose to counsel women about possible elevated risk

Because the Million Women Study is an observational study, with HRT exposure reported by participants, selection bias is possible (ie, respondents with ovarian cancer may be more likely to report HRT use). With this caveat, some clinicians may choose to counsel women that more than 5 years of unopposed estrogen or combination HRT may increase the risk of ovarian cancer, just as combination HRT raises the risk of breast cancer. A shorter duration of HRT does not appear to increase the risk of ovarian cancer and will probably serve the needs of many symptomatic, newly menopausal women.

<huc>A.</huc>Yes. In this study from France, the association between estrogen–progestin regimens and breast cancer varied significantly, depending on the progestin. The relative risk of invasive breast cancer was 1.08 for progesterone (95% confidence interval 0.89–1.31), 1.16 for dydrogesterone (0.94–1.43), and 1.69 for other progestins (1.50–1.91).

Expert Commentary

Fear of breast cancer discourages many women from using menopausal hormone therapy (HT), and fuels anxiety among patients and physicians alike. A large body of evidence from clinical trials and observational studies indicates that the use of estrogen-only therapy for less than 5 years has minimal, if any, impact on the risk of breast cancer.^1-5 In contrast, use of combination estrogen–progestin hormone therapy for more than 5 years is associated with an elevated risk of breast cancer,^3,6,7 and this risk is greater than the risk associated with the use of estrogen alone. This modestly increased risk is comparable to the elevated risk of breast cancer associated with lifestyle choices such as daily alcohol use, postmenopausal obesity, and lack of regular exercise.⁸

Few have focused on effects of specific progestins

Because the addition of a progestin to estrogen therapy in women with a uterus appears to play a key role in increasing the risk of breast cancer, and because a variety of progestins are available (including levonorgestrel, medroxyprogesterone acetate [MPA], norethindrone acetate, and progesterone), it makes sense to ask whether some progestins increase the risk of breast cancer more than others.

Although MPA is the most widely used progestin in menopausal practice in this country—and was the progestin used in the Women’s Health Initiative (WHI) trial of combination HT—other progestins are more common in Europe. The evidence has not definitively demonstrated that the choice of progestin affects the degree of breast cancer risk in women using HT.³

Large French population had high rate of HT use

HT is commonly used by menopausal women in France, and progesterone is the most widely prescribed progestin for endometrial protection, as Fournier and colleagues note. They conducted this large, prospective cohort study to assess HT use and breast cancer risk in almost 100,000 French teachers and wives of teachers, with intriguing results. Among the women followed in this study, 70% had used HT. The mean age at initiation was 52.4 years, and the mean duration of use and followup was 7 and 8.1 years, respectively.

Findings in regard to estrogen differ from those of other studies

Overall, the risk of being diagnosed with invasive breast cancer was significantly elevated with the use of estrogen alone, at a relative risk of 1.29 (95% confidence interval 1.02–1.65). This small elevation contrasts the findings of the WHI and Nurses’ Health studies, which identified no increased risk of breast cancer with estrogen alone.^4,5

Transdermal estrogen is widely used in menopausal women in France; route of estrogen administration did not affect breast cancer risk in this study.

Progesterone was associated with no elevated risk

The use of combination HT with MPA or norethindrone acetate was associated with higher relative risks than estrogen alone: 1.48 (1.02–2.16) and 2.11 (1.56–2.86), respectively. In contrast, combination HT with progesterone was not associated with an elevated risk of breast cancer, with a relative risk of 1.08 (0.89–1.31).

Fournier and colleagues point out that theirs is the first epidemiologic study to assess the risk of breast cancer associated with HT containing progesterone. They also cite recent data in postmenopausal primates indicating that combination HT with micronized progesterone causes lower rates of proliferation in lobular and ductal breast epithelium, compared with MPA-based hormone therapy.⁹

Clinical recommendations: For now, simply ensure adequate progestin

The findings of a single study generally should not dictate clinical practice. It remains the standard of care to ensure sufficient progestin (whether levonorgestrel, MPA, norethindrone acetate, or micronized progesterone) to prevent endometrial hyperplasia when prescribing HT for menopausal women with a uterus.

The findings of this study raise the possibility that progesterone may be safer than other progestins with respect to breast neoplasia. Additional epidemiologic data assessing the safety of progesterone in comparison with other progestins are welcome, but studies would need to be conducted in regions like France, where progesterone is widely used.

In the meantime, ObGyns who wish to prescribe micronized progesterone as part of combination HT should rule out peanut allergy and advise patients to take the micronized tablets at bedtime because of their tendency to cause sleepiness. The appropriate dosage of micronized progesterone to prevent endometrial proliferation in menopausal women using estrogen is 100 mg nightly or 200 mg cyclically for 12 or more days each month.¹⁰

<huc>A.</huc>Yes. In this study from France, the association between estrogen–progestin regimens and breast cancer varied significantly, depending on the progestin. The relative risk of invasive breast cancer was 1.08 for progesterone (95% confidence interval 0.89–1.31), 1.16 for dydrogesterone (0.94–1.43), and 1.69 for other progestins (1.50–1.91).

Expert Commentary

Fear of breast cancer discourages many women from using menopausal hormone therapy (HT), and fuels anxiety among patients and physicians alike. A large body of evidence from clinical trials and observational studies indicates that the use of estrogen-only therapy for less than 5 years has minimal, if any, impact on the risk of breast cancer.^1-5 In contrast, use of combination estrogen–progestin hormone therapy for more than 5 years is associated with an elevated risk of breast cancer,^3,6,7 and this risk is greater than the risk associated with the use of estrogen alone. This modestly increased risk is comparable to the elevated risk of breast cancer associated with lifestyle choices such as daily alcohol use, postmenopausal obesity, and lack of regular exercise.⁸

Few have focused on effects of specific progestins

Because the addition of a progestin to estrogen therapy in women with a uterus appears to play a key role in increasing the risk of breast cancer, and because a variety of progestins are available (including levonorgestrel, medroxyprogesterone acetate [MPA], norethindrone acetate, and progesterone), it makes sense to ask whether some progestins increase the risk of breast cancer more than others.

Although MPA is the most widely used progestin in menopausal practice in this country—and was the progestin used in the Women’s Health Initiative (WHI) trial of combination HT—other progestins are more common in Europe. The evidence has not definitively demonstrated that the choice of progestin affects the degree of breast cancer risk in women using HT.³

Large French population had high rate of HT use

HT is commonly used by menopausal women in France, and progesterone is the most widely prescribed progestin for endometrial protection, as Fournier and colleagues note. They conducted this large, prospective cohort study to assess HT use and breast cancer risk in almost 100,000 French teachers and wives of teachers, with intriguing results. Among the women followed in this study, 70% had used HT. The mean age at initiation was 52.4 years, and the mean duration of use and followup was 7 and 8.1 years, respectively.

Findings in regard to estrogen differ from those of other studies

Overall, the risk of being diagnosed with invasive breast cancer was significantly elevated with the use of estrogen alone, at a relative risk of 1.29 (95% confidence interval 1.02–1.65). This small elevation contrasts the findings of the WHI and Nurses’ Health studies, which identified no increased risk of breast cancer with estrogen alone.^4,5

Transdermal estrogen is widely used in menopausal women in France; route of estrogen administration did not affect breast cancer risk in this study.

Progesterone was associated with no elevated risk

The use of combination HT with MPA or norethindrone acetate was associated with higher relative risks than estrogen alone: 1.48 (1.02–2.16) and 2.11 (1.56–2.86), respectively. In contrast, combination HT with progesterone was not associated with an elevated risk of breast cancer, with a relative risk of 1.08 (0.89–1.31).

Fournier and colleagues point out that theirs is the first epidemiologic study to assess the risk of breast cancer associated with HT containing progesterone. They also cite recent data in postmenopausal primates indicating that combination HT with micronized progesterone causes lower rates of proliferation in lobular and ductal breast epithelium, compared with MPA-based hormone therapy.⁹

Clinical recommendations: For now, simply ensure adequate progestin

The findings of a single study generally should not dictate clinical practice. It remains the standard of care to ensure sufficient progestin (whether levonorgestrel, MPA, norethindrone acetate, or micronized progesterone) to prevent endometrial hyperplasia when prescribing HT for menopausal women with a uterus.

The findings of this study raise the possibility that progesterone may be safer than other progestins with respect to breast neoplasia. Additional epidemiologic data assessing the safety of progesterone in comparison with other progestins are welcome, but studies would need to be conducted in regions like France, where progesterone is widely used.

In the meantime, ObGyns who wish to prescribe micronized progesterone as part of combination HT should rule out peanut allergy and advise patients to take the micronized tablets at bedtime because of their tendency to cause sleepiness. The appropriate dosage of micronized progesterone to prevent endometrial proliferation in menopausal women using estrogen is 100 mg nightly or 200 mg cyclically for 12 or more days each month.¹⁰

<huc>A.</huc>Yes. In this study from France, the association between estrogen–progestin regimens and breast cancer varied significantly, depending on the progestin. The relative risk of invasive breast cancer was 1.08 for progesterone (95% confidence interval 0.89–1.31), 1.16 for dydrogesterone (0.94–1.43), and 1.69 for other progestins (1.50–1.91).

Expert Commentary

Fear of breast cancer discourages many women from using menopausal hormone therapy (HT), and fuels anxiety among patients and physicians alike. A large body of evidence from clinical trials and observational studies indicates that the use of estrogen-only therapy for less than 5 years has minimal, if any, impact on the risk of breast cancer.^1-5 In contrast, use of combination estrogen–progestin hormone therapy for more than 5 years is associated with an elevated risk of breast cancer,^3,6,7 and this risk is greater than the risk associated with the use of estrogen alone. This modestly increased risk is comparable to the elevated risk of breast cancer associated with lifestyle choices such as daily alcohol use, postmenopausal obesity, and lack of regular exercise.⁸

Few have focused on effects of specific progestins

Because the addition of a progestin to estrogen therapy in women with a uterus appears to play a key role in increasing the risk of breast cancer, and because a variety of progestins are available (including levonorgestrel, medroxyprogesterone acetate [MPA], norethindrone acetate, and progesterone), it makes sense to ask whether some progestins increase the risk of breast cancer more than others.

Although MPA is the most widely used progestin in menopausal practice in this country—and was the progestin used in the Women’s Health Initiative (WHI) trial of combination HT—other progestins are more common in Europe. The evidence has not definitively demonstrated that the choice of progestin affects the degree of breast cancer risk in women using HT.³

Large French population had high rate of HT use

HT is commonly used by menopausal women in France, and progesterone is the most widely prescribed progestin for endometrial protection, as Fournier and colleagues note. They conducted this large, prospective cohort study to assess HT use and breast cancer risk in almost 100,000 French teachers and wives of teachers, with intriguing results. Among the women followed in this study, 70% had used HT. The mean age at initiation was 52.4 years, and the mean duration of use and followup was 7 and 8.1 years, respectively.

Findings in regard to estrogen differ from those of other studies

Overall, the risk of being diagnosed with invasive breast cancer was significantly elevated with the use of estrogen alone, at a relative risk of 1.29 (95% confidence interval 1.02–1.65). This small elevation contrasts the findings of the WHI and Nurses’ Health studies, which identified no increased risk of breast cancer with estrogen alone.^4,5

Transdermal estrogen is widely used in menopausal women in France; route of estrogen administration did not affect breast cancer risk in this study.

Progesterone was associated with no elevated risk

The use of combination HT with MPA or norethindrone acetate was associated with higher relative risks than estrogen alone: 1.48 (1.02–2.16) and 2.11 (1.56–2.86), respectively. In contrast, combination HT with progesterone was not associated with an elevated risk of breast cancer, with a relative risk of 1.08 (0.89–1.31).

Fournier and colleagues point out that theirs is the first epidemiologic study to assess the risk of breast cancer associated with HT containing progesterone. They also cite recent data in postmenopausal primates indicating that combination HT with micronized progesterone causes lower rates of proliferation in lobular and ductal breast epithelium, compared with MPA-based hormone therapy.⁹

Clinical recommendations: For now, simply ensure adequate progestin

The findings of a single study generally should not dictate clinical practice. It remains the standard of care to ensure sufficient progestin (whether levonorgestrel, MPA, norethindrone acetate, or micronized progesterone) to prevent endometrial hyperplasia when prescribing HT for menopausal women with a uterus.

The findings of this study raise the possibility that progesterone may be safer than other progestins with respect to breast neoplasia. Additional epidemiologic data assessing the safety of progesterone in comparison with other progestins are welcome, but studies would need to be conducted in regions like France, where progesterone is widely used.

In the meantime, ObGyns who wish to prescribe micronized progesterone as part of combination HT should rule out peanut allergy and advise patients to take the micronized tablets at bedtime because of their tendency to cause sleepiness. The appropriate dosage of micronized progesterone to prevent endometrial proliferation in menopausal women using estrogen is 100 mg nightly or 200 mg cyclically for 12 or more days each month.¹⁰

A.Maybe. Rosiglitazone outperformed metformin in this small sample of obese women with polycystic ovary syndrome (PCOS). On average, it improved unbound testosterone, 2-hour glucose and 2-hour insulin levels, and the daily urinary progestin-to-estrogen ratio. Ovulation increased on both drugs, alone and in combination, but 5 of 16 women showed no evidence of ovulation after 6 months.

Expert Commentary

Insulin resistance is central to the anovulation and hyperandrogenism of many women with PCOS, and insulin-sensitizing drugs are increasingly used for chronic treatment, especially to ameliorate the metabolic sequelae of type 2 diabetes and cardiovascular disease. In the diabetes world, combining insulin-sensitizing drugs of different classes yields superior results, compared with monotherapy.

On this basis, Legro and colleagues conducted a pilot study to compare the effects of metformin and rosiglitazone, alone and in combination, on ovulation, androgens, and endometrial histology in women with PCOS. Women were randomized to metformin or rosiglitazone monotherapy for 12 weeks, followed by 12 weeks of combination therapy.

Researchers used urinary pregnanediol-3-glucuronide to detect ovulation, and did periodic endometrial biopsies.

Duration of study was insufficient

Metformin may take as long as 6 months to exert an optimal effect on ovulation, and thiazolidinediones (including rosiglitazone) may require 3 to 4 months to improve insulin sensitivity. Therefore, neither drug was given for a sufficient duration to assess its individual effects.

In this study, the number of subjects was small (5 women completed the metformin arm, and 9 women the rosiglitazone arm), and the groups differed greatly at baseline, with the metformin group being heavier and the rosiglitazone group being more hirsute and having higher serum testosterone and insulin levels. These baseline differences make comparison of the 2 groups after 3 months of monotherapy difficult, because the seeming improvements in testosterone and insulin in the rosiglitazone group may have been due to regression to the mean rather than a true effect of the drug.

Both drugs improved ovulation. Combining the 2 drugs did not add further benefit, but lack of benefit may have been the result of the brief duration of combined therapy (12 weeks).

Both drugs tended to normalize endometrial histology in the women who had simple hyperplasia at baseline. The number of women was small, but the finding is buttressed by 2 earlier studies in PCOS showing that metformin improves uterine vascularity and circulating glycodelin, a marker of endometrial function.^1,2

No change to clinical practice—yet

As a pilot study, the trial was not meant to change clinical practice—nor should it. The future trial resulting from this pilot study should incorporate longer durations of treatment and yield more answers.

A.Maybe. Rosiglitazone outperformed metformin in this small sample of obese women with polycystic ovary syndrome (PCOS). On average, it improved unbound testosterone, 2-hour glucose and 2-hour insulin levels, and the daily urinary progestin-to-estrogen ratio. Ovulation increased on both drugs, alone and in combination, but 5 of 16 women showed no evidence of ovulation after 6 months.

Expert Commentary

Insulin resistance is central to the anovulation and hyperandrogenism of many women with PCOS, and insulin-sensitizing drugs are increasingly used for chronic treatment, especially to ameliorate the metabolic sequelae of type 2 diabetes and cardiovascular disease. In the diabetes world, combining insulin-sensitizing drugs of different classes yields superior results, compared with monotherapy.

On this basis, Legro and colleagues conducted a pilot study to compare the effects of metformin and rosiglitazone, alone and in combination, on ovulation, androgens, and endometrial histology in women with PCOS. Women were randomized to metformin or rosiglitazone monotherapy for 12 weeks, followed by 12 weeks of combination therapy.

Researchers used urinary pregnanediol-3-glucuronide to detect ovulation, and did periodic endometrial biopsies.

Duration of study was insufficient

Metformin may take as long as 6 months to exert an optimal effect on ovulation, and thiazolidinediones (including rosiglitazone) may require 3 to 4 months to improve insulin sensitivity. Therefore, neither drug was given for a sufficient duration to assess its individual effects.

In this study, the number of subjects was small (5 women completed the metformin arm, and 9 women the rosiglitazone arm), and the groups differed greatly at baseline, with the metformin group being heavier and the rosiglitazone group being more hirsute and having higher serum testosterone and insulin levels. These baseline differences make comparison of the 2 groups after 3 months of monotherapy difficult, because the seeming improvements in testosterone and insulin in the rosiglitazone group may have been due to regression to the mean rather than a true effect of the drug.

Both drugs improved ovulation. Combining the 2 drugs did not add further benefit, but lack of benefit may have been the result of the brief duration of combined therapy (12 weeks).

Both drugs tended to normalize endometrial histology in the women who had simple hyperplasia at baseline. The number of women was small, but the finding is buttressed by 2 earlier studies in PCOS showing that metformin improves uterine vascularity and circulating glycodelin, a marker of endometrial function.^1,2

No change to clinical practice—yet

As a pilot study, the trial was not meant to change clinical practice—nor should it. The future trial resulting from this pilot study should incorporate longer durations of treatment and yield more answers.

A.Maybe. Rosiglitazone outperformed metformin in this small sample of obese women with polycystic ovary syndrome (PCOS). On average, it improved unbound testosterone, 2-hour glucose and 2-hour insulin levels, and the daily urinary progestin-to-estrogen ratio. Ovulation increased on both drugs, alone and in combination, but 5 of 16 women showed no evidence of ovulation after 6 months.

Expert Commentary

Insulin resistance is central to the anovulation and hyperandrogenism of many women with PCOS, and insulin-sensitizing drugs are increasingly used for chronic treatment, especially to ameliorate the metabolic sequelae of type 2 diabetes and cardiovascular disease. In the diabetes world, combining insulin-sensitizing drugs of different classes yields superior results, compared with monotherapy.

On this basis, Legro and colleagues conducted a pilot study to compare the effects of metformin and rosiglitazone, alone and in combination, on ovulation, androgens, and endometrial histology in women with PCOS. Women were randomized to metformin or rosiglitazone monotherapy for 12 weeks, followed by 12 weeks of combination therapy.

Researchers used urinary pregnanediol-3-glucuronide to detect ovulation, and did periodic endometrial biopsies.

Duration of study was insufficient

Metformin may take as long as 6 months to exert an optimal effect on ovulation, and thiazolidinediones (including rosiglitazone) may require 3 to 4 months to improve insulin sensitivity. Therefore, neither drug was given for a sufficient duration to assess its individual effects.

In this study, the number of subjects was small (5 women completed the metformin arm, and 9 women the rosiglitazone arm), and the groups differed greatly at baseline, with the metformin group being heavier and the rosiglitazone group being more hirsute and having higher serum testosterone and insulin levels. These baseline differences make comparison of the 2 groups after 3 months of monotherapy difficult, because the seeming improvements in testosterone and insulin in the rosiglitazone group may have been due to regression to the mean rather than a true effect of the drug.

Both drugs improved ovulation. Combining the 2 drugs did not add further benefit, but lack of benefit may have been the result of the brief duration of combined therapy (12 weeks).

Both drugs tended to normalize endometrial histology in the women who had simple hyperplasia at baseline. The number of women was small, but the finding is buttressed by 2 earlier studies in PCOS showing that metformin improves uterine vascularity and circulating glycodelin, a marker of endometrial function.^1,2

No change to clinical practice—yet

As a pilot study, the trial was not meant to change clinical practice—nor should it. The future trial resulting from this pilot study should incorporate longer durations of treatment and yield more answers.

A.Not according to this analysis of data from Massachusetts. It found that women who planned primary cesarean delivery were 2.3 times more likely to be rehospitalized within 30 days than were women who planned vaginal delivery.

Expert Commentary

Declercq and colleagues utilized a state-based data system linking birth certificates, fetal death records, and birth-related hospital discharge records from 1998 to 2003. Their study included 244,088 women (240,754 planned vaginal deliveries and 3,334 planned cesareans) with no previous cesarean and no documented prenatal risk.

Annually, about 1.2 million American women deliver by cesarean section, the most commonly performed major abdominal surgery in the nation. Yet we know surprisingly little about the phenomenon of women requesting cesareans without a medical or obstetric indication. There is no question that cesarean delivery on maternal request (CDMR) is a topic of great controversy. Despite considerable interest in the subject, there are very few data to guide practitioners.

The difficulty of comparing planned cesarean and vaginal deliveries

This study has several limitations, which are acknowledged by the authors:

• Data derived from hospital discharge records and birth certificates have limitations. The 2 groups compared in this study were reconstructed from hospital records, and the planned mode of delivery was determined retrospectively. For these reasons, the planned primary cesarean group may be an inaccurate measure and oversimplification of maternal request.
  
• The cesarean delivery rate in the planned vaginal birth group was low at 8.7%, compared with the overall national primary cesarean rate of 20.6% in 2004.¹ This suggests that the selection of patients for inclusion in this study may have been subject to bias.
  
• Using an intent-to-treat analysis, the authors included women with planned vaginal birth who delivered via unplanned primary cesarean section, but failed to include the converse: women with planned cesarean delivery who presented in labor. Although mothers with labored cesareans constitute a small group, they are known to be exposed to higher complication rates than are women with unlabored cesareans.
  
• The primary reason for hospitalization was wound infection, and this study did not adjust for other important confounders for this complication, such as obesity.
  

In general, findings do not change those of the NIH panel on CDMR

This study highlights the paucity of literature on CDMR and the need for better prospective data. In a state-of-the-science conference on CDMR, sponsored by the National Institutes of Health in March 2006, a systematic review of the literature found weak evidence supporting a lower infection rate with vaginal delivery, compared with planned or unplanned cesarean.² In our view, the study by Declercq and colleagues does not change the weak nature of evidence, but corroborates the impression of many practitioners that, in general, cesarean delivery is associated with higher rates of infectious morbidity than vaginal birth.

Although rehospitalization remains an important complication of cesarean section, the choice of delivery method is complex and involves numerous other factors such as ethics, fetal and neonatal morbidity, cultural background, professional resources, concerns about pelvic floor injury, and the risk of abnormal placentation in future pregnancies.

Bottom line: Individualize the decision

When a patient inquires about CDMR, the practitioner should carefully individualize the decision consistent with ethical principles and informed consent, while taking into account the available medical and health resources and the patient’s preferences. Unfortunately, there is little clear guidance we can offer women considering CDMR because there are major gaps in our information.

Sorely needed is a comprehensive, nationwide research effort to more precisely understand the risks and benefits—for both mother and child—of cesarean delivery on maternal request as compared with both planned vaginal delivery and medically advised cesarean section. We owe the women and children of this nation nothing less.

A.Not according to this analysis of data from Massachusetts. It found that women who planned primary cesarean delivery were 2.3 times more likely to be rehospitalized within 30 days than were women who planned vaginal delivery.

Expert Commentary

Declercq and colleagues utilized a state-based data system linking birth certificates, fetal death records, and birth-related hospital discharge records from 1998 to 2003. Their study included 244,088 women (240,754 planned vaginal deliveries and 3,334 planned cesareans) with no previous cesarean and no documented prenatal risk.

Annually, about 1.2 million American women deliver by cesarean section, the most commonly performed major abdominal surgery in the nation. Yet we know surprisingly little about the phenomenon of women requesting cesareans without a medical or obstetric indication. There is no question that cesarean delivery on maternal request (CDMR) is a topic of great controversy. Despite considerable interest in the subject, there are very few data to guide practitioners.

The difficulty of comparing planned cesarean and vaginal deliveries

This study has several limitations, which are acknowledged by the authors:

• Data derived from hospital discharge records and birth certificates have limitations. The 2 groups compared in this study were reconstructed from hospital records, and the planned mode of delivery was determined retrospectively. For these reasons, the planned primary cesarean group may be an inaccurate measure and oversimplification of maternal request.
  
• The cesarean delivery rate in the planned vaginal birth group was low at 8.7%, compared with the overall national primary cesarean rate of 20.6% in 2004.¹ This suggests that the selection of patients for inclusion in this study may have been subject to bias.
  
• Using an intent-to-treat analysis, the authors included women with planned vaginal birth who delivered via unplanned primary cesarean section, but failed to include the converse: women with planned cesarean delivery who presented in labor. Although mothers with labored cesareans constitute a small group, they are known to be exposed to higher complication rates than are women with unlabored cesareans.
  
• The primary reason for hospitalization was wound infection, and this study did not adjust for other important confounders for this complication, such as obesity.
  

In general, findings do not change those of the NIH panel on CDMR

This study highlights the paucity of literature on CDMR and the need for better prospective data. In a state-of-the-science conference on CDMR, sponsored by the National Institutes of Health in March 2006, a systematic review of the literature found weak evidence supporting a lower infection rate with vaginal delivery, compared with planned or unplanned cesarean.² In our view, the study by Declercq and colleagues does not change the weak nature of evidence, but corroborates the impression of many practitioners that, in general, cesarean delivery is associated with higher rates of infectious morbidity than vaginal birth.

Although rehospitalization remains an important complication of cesarean section, the choice of delivery method is complex and involves numerous other factors such as ethics, fetal and neonatal morbidity, cultural background, professional resources, concerns about pelvic floor injury, and the risk of abnormal placentation in future pregnancies.

Bottom line: Individualize the decision

When a patient inquires about CDMR, the practitioner should carefully individualize the decision consistent with ethical principles and informed consent, while taking into account the available medical and health resources and the patient’s preferences. Unfortunately, there is little clear guidance we can offer women considering CDMR because there are major gaps in our information.

Sorely needed is a comprehensive, nationwide research effort to more precisely understand the risks and benefits—for both mother and child—of cesarean delivery on maternal request as compared with both planned vaginal delivery and medically advised cesarean section. We owe the women and children of this nation nothing less.

A.Not according to this analysis of data from Massachusetts. It found that women who planned primary cesarean delivery were 2.3 times more likely to be rehospitalized within 30 days than were women who planned vaginal delivery.

Expert Commentary

Declercq and colleagues utilized a state-based data system linking birth certificates, fetal death records, and birth-related hospital discharge records from 1998 to 2003. Their study included 244,088 women (240,754 planned vaginal deliveries and 3,334 planned cesareans) with no previous cesarean and no documented prenatal risk.

Annually, about 1.2 million American women deliver by cesarean section, the most commonly performed major abdominal surgery in the nation. Yet we know surprisingly little about the phenomenon of women requesting cesareans without a medical or obstetric indication. There is no question that cesarean delivery on maternal request (CDMR) is a topic of great controversy. Despite considerable interest in the subject, there are very few data to guide practitioners.

The difficulty of comparing planned cesarean and vaginal deliveries

This study has several limitations, which are acknowledged by the authors:

• Data derived from hospital discharge records and birth certificates have limitations. The 2 groups compared in this study were reconstructed from hospital records, and the planned mode of delivery was determined retrospectively. For these reasons, the planned primary cesarean group may be an inaccurate measure and oversimplification of maternal request.
  
• The cesarean delivery rate in the planned vaginal birth group was low at 8.7%, compared with the overall national primary cesarean rate of 20.6% in 2004.¹ This suggests that the selection of patients for inclusion in this study may have been subject to bias.
  
• Using an intent-to-treat analysis, the authors included women with planned vaginal birth who delivered via unplanned primary cesarean section, but failed to include the converse: women with planned cesarean delivery who presented in labor. Although mothers with labored cesareans constitute a small group, they are known to be exposed to higher complication rates than are women with unlabored cesareans.
  
• The primary reason for hospitalization was wound infection, and this study did not adjust for other important confounders for this complication, such as obesity.
  

In general, findings do not change those of the NIH panel on CDMR

This study highlights the paucity of literature on CDMR and the need for better prospective data. In a state-of-the-science conference on CDMR, sponsored by the National Institutes of Health in March 2006, a systematic review of the literature found weak evidence supporting a lower infection rate with vaginal delivery, compared with planned or unplanned cesarean.² In our view, the study by Declercq and colleagues does not change the weak nature of evidence, but corroborates the impression of many practitioners that, in general, cesarean delivery is associated with higher rates of infectious morbidity than vaginal birth.

Although rehospitalization remains an important complication of cesarean section, the choice of delivery method is complex and involves numerous other factors such as ethics, fetal and neonatal morbidity, cultural background, professional resources, concerns about pelvic floor injury, and the risk of abnormal placentation in future pregnancies.

Bottom line: Individualize the decision

When a patient inquires about CDMR, the practitioner should carefully individualize the decision consistent with ethical principles and informed consent, while taking into account the available medical and health resources and the patient’s preferences. Unfortunately, there is little clear guidance we can offer women considering CDMR because there are major gaps in our information.

Sorely needed is a comprehensive, nationwide research effort to more precisely understand the risks and benefits—for both mother and child—of cesarean delivery on maternal request as compared with both planned vaginal delivery and medically advised cesarean section. We owe the women and children of this nation nothing less.

A.No. In this retrospective family cohort study from the Netherlands, women who had protein S, protein C, or antithrombin deficiency had a greater baseline risk of venous thromboembolism (VTE), and the risk increased when they used combination oral contraceptives.

Expert Commentary

This report confirms the greater risk of VTE in women with protein S, protein C, or antithrombin deficiency, compared with unaffected women. When they used oral contraceptives (OCs), women with 1 or more of these deficiencies had 10 times the risk of VTE that unaffected women had. And when they had additional thrombophilic deficiencies—such as a second deficiency of protein S or C or antithrombin; factor V Leiden; or prothrombin G20210A—their risk of VTE was further amplified.

Because women with thrombophilic deficiency have a higher baseline risk of VTE, they developed VTE while taking OCs—or during pregnancy, another high-risk setting—at a younger age than their non–OC-using or nonpregnant counterparts, but the overall incidence of VTE during their reproductive years did not increase.

Family cohort framework facilitated study of rare mutations

A retrospective family cohort study is a good design to control for events in similar populations with relatively rare mutational occurrences. This study was adequately powered for its major observations, but lost power and significance when it focused on women with multiple thrombophilic deficiencies. Nevertheless, it confirmed the greater risk of VTE with OC use in thrombophilic women, and clarified the absolute risk of VTE over a woman’s reproductive life, which remains fairly stable because women with thrombophilic deficiencies are at such high risk to begin with.

The study also demonstrated that women with a thrombophilic deficiency have a high risk of multiple deficiencies.

Findings may not be applicable to women with other deficiencies

When a woman has a deficiency other than protein S, protein C, or antithrombin, these findings may not be valid. For example, factor V Leiden mutation is strongly associated with VTE in OC users. It is unclear whether the observation of a stable absolute risk of VTE in OC users would have held up if factor V Leiden was one of the major deficiencies studied.

Bottom line: Pay attention to the family history

This study highlights the importance of a good family history. Women who have family members known to have a thrombophilic deficiency should avoid OCs or be tested for all deficiencies and given oral contraceptives only if they prove to be free of deficiencies. These tests are very expensive and are not cost-effective in a general population screen.

A.No. In this retrospective family cohort study from the Netherlands, women who had protein S, protein C, or antithrombin deficiency had a greater baseline risk of venous thromboembolism (VTE), and the risk increased when they used combination oral contraceptives.

Expert Commentary

This report confirms the greater risk of VTE in women with protein S, protein C, or antithrombin deficiency, compared with unaffected women. When they used oral contraceptives (OCs), women with 1 or more of these deficiencies had 10 times the risk of VTE that unaffected women had. And when they had additional thrombophilic deficiencies—such as a second deficiency of protein S or C or antithrombin; factor V Leiden; or prothrombin G20210A—their risk of VTE was further amplified.

Because women with thrombophilic deficiency have a higher baseline risk of VTE, they developed VTE while taking OCs—or during pregnancy, another high-risk setting—at a younger age than their non–OC-using or nonpregnant counterparts, but the overall incidence of VTE during their reproductive years did not increase.

Family cohort framework facilitated study of rare mutations

A retrospective family cohort study is a good design to control for events in similar populations with relatively rare mutational occurrences. This study was adequately powered for its major observations, but lost power and significance when it focused on women with multiple thrombophilic deficiencies. Nevertheless, it confirmed the greater risk of VTE with OC use in thrombophilic women, and clarified the absolute risk of VTE over a woman’s reproductive life, which remains fairly stable because women with thrombophilic deficiencies are at such high risk to begin with.

The study also demonstrated that women with a thrombophilic deficiency have a high risk of multiple deficiencies.

Findings may not be applicable to women with other deficiencies

When a woman has a deficiency other than protein S, protein C, or antithrombin, these findings may not be valid. For example, factor V Leiden mutation is strongly associated with VTE in OC users. It is unclear whether the observation of a stable absolute risk of VTE in OC users would have held up if factor V Leiden was one of the major deficiencies studied.

Bottom line: Pay attention to the family history

This study highlights the importance of a good family history. Women who have family members known to have a thrombophilic deficiency should avoid OCs or be tested for all deficiencies and given oral contraceptives only if they prove to be free of deficiencies. These tests are very expensive and are not cost-effective in a general population screen.

A.No. In this retrospective family cohort study from the Netherlands, women who had protein S, protein C, or antithrombin deficiency had a greater baseline risk of venous thromboembolism (VTE), and the risk increased when they used combination oral contraceptives.

Expert Commentary

This report confirms the greater risk of VTE in women with protein S, protein C, or antithrombin deficiency, compared with unaffected women. When they used oral contraceptives (OCs), women with 1 or more of these deficiencies had 10 times the risk of VTE that unaffected women had. And when they had additional thrombophilic deficiencies—such as a second deficiency of protein S or C or antithrombin; factor V Leiden; or prothrombin G20210A—their risk of VTE was further amplified.

Because women with thrombophilic deficiency have a higher baseline risk of VTE, they developed VTE while taking OCs—or during pregnancy, another high-risk setting—at a younger age than their non–OC-using or nonpregnant counterparts, but the overall incidence of VTE during their reproductive years did not increase.

Family cohort framework facilitated study of rare mutations

A retrospective family cohort study is a good design to control for events in similar populations with relatively rare mutational occurrences. This study was adequately powered for its major observations, but lost power and significance when it focused on women with multiple thrombophilic deficiencies. Nevertheless, it confirmed the greater risk of VTE with OC use in thrombophilic women, and clarified the absolute risk of VTE over a woman’s reproductive life, which remains fairly stable because women with thrombophilic deficiencies are at such high risk to begin with.

The study also demonstrated that women with a thrombophilic deficiency have a high risk of multiple deficiencies.

Findings may not be applicable to women with other deficiencies

When a woman has a deficiency other than protein S, protein C, or antithrombin, these findings may not be valid. For example, factor V Leiden mutation is strongly associated with VTE in OC users. It is unclear whether the observation of a stable absolute risk of VTE in OC users would have held up if factor V Leiden was one of the major deficiencies studied.

Bottom line: Pay attention to the family history

This study highlights the importance of a good family history. Women who have family members known to have a thrombophilic deficiency should avoid OCs or be tested for all deficiencies and given oral contraceptives only if they prove to be free of deficiencies. These tests are very expensive and are not cost-effective in a general population screen.

A. Clomiphene is superior to metformin in achieving live births in infertile women with polycystic ovary syndrome (PCOS), but carries a higher risk of multiple gestation.

Expert Commentary

Frontline therapy for ovulation induction in women with PCOS has evolved from clomiphene to metformin, particularly since Palomba and colleagues¹ noted comparable ovulation rates and improved conception rates when metformin was given. This new report by Legro and colleagues from the Cooperative Multicenter Reproductive Medicine Network resoundingly contradicts that more limited report and reasserts the primacy of clomiphene in ovulation induction for PCOS. It is reminiscent of the Women’s Health Initiative, in that a well-designed large clinical trial has yielded findings opposite those theorized by investigators.

Legro and colleagues also report a reassuringly low multiple-pregnancy rate in the treatment groups that included clomiphene citrate, and no multiples in the metformin-only group. In addition, they demonstrate a clear, deleterious effect of extreme obesity (body mass index [BMI] greater than 35) on the efficacy of clomiphene and metformin individually and of the 2 agents combined.

Distinctive features of this trial

It is worth noting that the trial by Legro and colleagues contrasts the study by Palomba and associates in 2 critical design characteristics. First, Palomba and associates included only women with a BMI less than 30, whereas Legro and colleagues included a range of body sizes: Only 30% of participants were less than obese and nearly half were massively obese.

Second, the Palomba study was conducted in Italy, presumably in a more homogeneous population than the multiethnic, multicenter trial by Legro and colleagues. However, in the latter trial, even the subgroup analysis for the 179 subjects with a BMI less than 30 demonstrated the same relative proportions of ovulation and conception as the overall trial, albeit with higher rates than in heavier women.

The 2 studies also used slightly different criteria to document ovulation, and the study by Legro and colleagues used the more robust outcome of live birth rate as a primary endpoint—a much more clinically useful measure.

Nonetheless, these differences are insufficient to explain the striking contrast between the data from Legro and colleagues and virtually all of the limited recent work in this area, calling into question the recent move toward metformin as primary frontline therapy. The size, design, and multicenter nature of this trial demand that we consider it the primary source for level I evidence on the subject.

The greater the obesity, the lower the fertility

Perhaps an equally important finding of this study is the diminished response to metformin, clomiphene, or both in women with a BMI of 35 or above. This suggests that aggressive therapy up front may be warranted in these patients in addition to a coordinated plan of dietary and exercise therapy.

Bottom line: Use clomiphene first

This study points us back to the long-standing practice of using clomiphene citrate as frontline therapy for ovulation induction in women with PCOS, with the additional caveat that body size is a critical modifier of this therapy. However, the cumulative ovulation rate of about 40% and cumulative conception rate of about 20% in women with a BMI less than 35 taking metformin make that drug a reasonable frontline option for couples very concerned about multiple gestation or significant side effects with clomiphene.

A. Clomiphene is superior to metformin in achieving live births in infertile women with polycystic ovary syndrome (PCOS), but carries a higher risk of multiple gestation.

Expert Commentary

Frontline therapy for ovulation induction in women with PCOS has evolved from clomiphene to metformin, particularly since Palomba and colleagues¹ noted comparable ovulation rates and improved conception rates when metformin was given. This new report by Legro and colleagues from the Cooperative Multicenter Reproductive Medicine Network resoundingly contradicts that more limited report and reasserts the primacy of clomiphene in ovulation induction for PCOS. It is reminiscent of the Women’s Health Initiative, in that a well-designed large clinical trial has yielded findings opposite those theorized by investigators.

Legro and colleagues also report a reassuringly low multiple-pregnancy rate in the treatment groups that included clomiphene citrate, and no multiples in the metformin-only group. In addition, they demonstrate a clear, deleterious effect of extreme obesity (body mass index [BMI] greater than 35) on the efficacy of clomiphene and metformin individually and of the 2 agents combined.

Distinctive features of this trial

It is worth noting that the trial by Legro and colleagues contrasts the study by Palomba and associates in 2 critical design characteristics. First, Palomba and associates included only women with a BMI less than 30, whereas Legro and colleagues included a range of body sizes: Only 30% of participants were less than obese and nearly half were massively obese.

Second, the Palomba study was conducted in Italy, presumably in a more homogeneous population than the multiethnic, multicenter trial by Legro and colleagues. However, in the latter trial, even the subgroup analysis for the 179 subjects with a BMI less than 30 demonstrated the same relative proportions of ovulation and conception as the overall trial, albeit with higher rates than in heavier women.

The 2 studies also used slightly different criteria to document ovulation, and the study by Legro and colleagues used the more robust outcome of live birth rate as a primary endpoint—a much more clinically useful measure.

Nonetheless, these differences are insufficient to explain the striking contrast between the data from Legro and colleagues and virtually all of the limited recent work in this area, calling into question the recent move toward metformin as primary frontline therapy. The size, design, and multicenter nature of this trial demand that we consider it the primary source for level I evidence on the subject.

The greater the obesity, the lower the fertility

Perhaps an equally important finding of this study is the diminished response to metformin, clomiphene, or both in women with a BMI of 35 or above. This suggests that aggressive therapy up front may be warranted in these patients in addition to a coordinated plan of dietary and exercise therapy.

Bottom line: Use clomiphene first

This study points us back to the long-standing practice of using clomiphene citrate as frontline therapy for ovulation induction in women with PCOS, with the additional caveat that body size is a critical modifier of this therapy. However, the cumulative ovulation rate of about 40% and cumulative conception rate of about 20% in women with a BMI less than 35 taking metformin make that drug a reasonable frontline option for couples very concerned about multiple gestation or significant side effects with clomiphene.

A. Clomiphene is superior to metformin in achieving live births in infertile women with polycystic ovary syndrome (PCOS), but carries a higher risk of multiple gestation.

Expert Commentary

Frontline therapy for ovulation induction in women with PCOS has evolved from clomiphene to metformin, particularly since Palomba and colleagues¹ noted comparable ovulation rates and improved conception rates when metformin was given. This new report by Legro and colleagues from the Cooperative Multicenter Reproductive Medicine Network resoundingly contradicts that more limited report and reasserts the primacy of clomiphene in ovulation induction for PCOS. It is reminiscent of the Women’s Health Initiative, in that a well-designed large clinical trial has yielded findings opposite those theorized by investigators.

Legro and colleagues also report a reassuringly low multiple-pregnancy rate in the treatment groups that included clomiphene citrate, and no multiples in the metformin-only group. In addition, they demonstrate a clear, deleterious effect of extreme obesity (body mass index [BMI] greater than 35) on the efficacy of clomiphene and metformin individually and of the 2 agents combined.

Distinctive features of this trial

It is worth noting that the trial by Legro and colleagues contrasts the study by Palomba and associates in 2 critical design characteristics. First, Palomba and associates included only women with a BMI less than 30, whereas Legro and colleagues included a range of body sizes: Only 30% of participants were less than obese and nearly half were massively obese.

Second, the Palomba study was conducted in Italy, presumably in a more homogeneous population than the multiethnic, multicenter trial by Legro and colleagues. However, in the latter trial, even the subgroup analysis for the 179 subjects with a BMI less than 30 demonstrated the same relative proportions of ovulation and conception as the overall trial, albeit with higher rates than in heavier women.

The 2 studies also used slightly different criteria to document ovulation, and the study by Legro and colleagues used the more robust outcome of live birth rate as a primary endpoint—a much more clinically useful measure.

Nonetheless, these differences are insufficient to explain the striking contrast between the data from Legro and colleagues and virtually all of the limited recent work in this area, calling into question the recent move toward metformin as primary frontline therapy. The size, design, and multicenter nature of this trial demand that we consider it the primary source for level I evidence on the subject.

The greater the obesity, the lower the fertility

Perhaps an equally important finding of this study is the diminished response to metformin, clomiphene, or both in women with a BMI of 35 or above. This suggests that aggressive therapy up front may be warranted in these patients in addition to a coordinated plan of dietary and exercise therapy.

Bottom line: Use clomiphene first

This study points us back to the long-standing practice of using clomiphene citrate as frontline therapy for ovulation induction in women with PCOS, with the additional caveat that body size is a critical modifier of this therapy. However, the cumulative ovulation rate of about 40% and cumulative conception rate of about 20% in women with a BMI less than 35 taking metformin make that drug a reasonable frontline option for couples very concerned about multiple gestation or significant side effects with clomiphene.