Clinical Review

OBG Management Senior Editor Janelle Yates contributed to this article.

Hear Dr. Pinkerton discuss this article

The Women’s Health Initiative (WHI) caused a sea change in women’s attitudes toward menopausal hormone therapy and aroused many fears—not always rational—that remain almost palpable today. One study of the aftermath of the WHI found that 70% of women who were taking hormone therapy discontinued it, and 26% of women lost confidence in medical recommendations in general.¹

Into the chaos stepped Suzanne Somers, Michael Platt, and other celebrities, touting the benefits of a new kind of hormone: bioidentical. You don’t have to read Somers’ bestseller, The Sexy Years, to encounter the claims it makes on behalf of bioidenticals; the cover itself makes them clear: Discover the Hormone Connection—The Secret to Fabulous Sex, Great Health and Vitality, for Women and Men. Since publication of the book, the demand for bioidentical hormones has only increased, as women remain fearful about conventional hormone therapy.

Many ObGyns regularly field requests from patients for specially compounded bioidentical regimens. In most cases, the women who ask for these drugs are poorly informed about their risks and willing to pay out of pocket to acquire them. JoAnn V. Pinkerton, MD, sees many of these patients at The Women’s Place Midlife Health Center in Charlottesville, Virginia. OBG Management recently sat down with Dr. Pinkerton to discuss her concerns about the growing ubiquity of compounded bioidentical hormones. In the Q&A that follows, we talk about what “bioidentical” actually means, whether these hormones are ever justified, common misconceptions about them, and other issues.

In a special accompanying commentary, former Food and Drug Administration (FDA) Senior Medical Officer Bruce Patsner, MD, JD, also weighs in on the issue.

What is “bioidentical”?

OBG MANAGEMENT: Let’s start with the basics. What does the word “bioidentical” mean? Is it a legitimate medical term?

DR. PINKERTON: Bioidentical hormones are exogenous hormones that are biochemically similar to those produced endogenously by the body or ovaries. These include estrone, estradiol, estriol, progesterone, testosterone, dehydroepiandrosterone (DHEA), and cortisol. The FDA has approved many prescription products that contain bioidentical hormones. However, the term “bioidentical” is often used to refer to custom-compounded hormones. The major difference between the FDA-approved prescription bioidentical hormone products and custom-compounded products is that the former are regulated by the FDA and tested for purity, potency, efficacy, and safety.

Bioidenticals are not “natural” hormones, although many consumers think they are. In reality, compounded bioidentical hormones and FDA-approved bioidentical hormones all come from the same precursors. They begin as soy products or wild yam and then get converted to the different hormones in a laboratory in Germany before finding their way to the various world markets.

The claim that all bioidentical hormones are bioengineered to contain the same chemical structure as natural female sex hormones is false. As one expert noted, “the term ‘bioidentical’ has become inappropriately synonymous with ‘natural’ or ‘not synthetic’ and should be redefined to correct patient misconceptions.”²

Common misconceptions

OBG MANAGEMENT: What are some of the other false impressions you encounter among patients who ask for bioidenticals?

DR. PINKERTON: That the hormones are safer or more effective than hormone therapy, that they carry no risks, and that they are as well-monitored as FDA-approved products, to name a few. (For more, see “10 erroneous beliefs patients have about compounded hormones”).

OBG MANAGEMENT: Where do these ideas originate?

DR. PINKERTON: They are propagated by self-proclaimed experts and celebrities or by laypersons and physicians who devote the bulk of their time to promoting these hormones, usually at considerable cost to the patient.

OBG MANAGEMENT: What are the risks of compounded bioidentical hormones?

DR. PINKERTON: According to FDA guidance for industry, in the absence of data about these hormones, the risks and benefits should be assumed to be identical to those of FDA-approved hormone therapies, with the caveat that we don’t know from batch to batch what a woman is receiving. However, they are not regulated or monitored by the FDA, so we are lacking testing for purity, potency, efficacy, and safety. When the FDA did analyze compounded bioidentical hormones, a significant percentage (34%) failed one or more standard quality tests.³ In comparison, FDA-approved drugs fail analytical testing at a rate of less than 2%.³

The problems with compounded hormones

BRUCE PATSNER, MD, JD
Dr. Patsner is Research Professor of Law at the University of Houston Law Center in Houston, Tex. He served as Senior Medical Officer at the US Food and Drug Administration (FDA), where he was one of the agency’s experts on pharmacy compounding of prescription hormone drug therapy for the treatment of menopausal conditions.

The FDA has nothing against compounding pharmacies per se. Individualized preparation of a customized medication for a patient, based on a valid prescription, is an essential part of the practice of pharmacy. However, some actors in the pharmacy compounding business have taken the practice to a different level, not just in terms of the volume of business they do, but in the way compounded hormones are advertised and promoted. The courts aren’t necessarily interested in intervening in cases involving high volume alone. And when it comes to unsubstantiated claims of benefit, the FDA has found it difficult to assert jurisdiction over pharmacy compounding in general, making it hard to assert control over the advertising claims these pharmacies make on behalf of compounded drugs.

The result? The FDA has been unable to rein in claims that compounded prescription drugs are safer or better than commercially prepared medications. These drugs are probably as safe and effective as their manufactured counterparts, but there are no data to confirm this assumption.

What’s in a name?

“Bioidentical” isn’t a bona fide term. There is no definition of it in any medical dictionary; it’s just a name the industry cooked up, a catchy one at that. And when bioidenticals are advertised and promoted, the term “natural” is usually in close proximity. Most patients equate the word natural with plant-derived substances that have not been chemically altered. The fact is, many compounded prescription drugs are derived from plants—but they are also chemically altered.

Some applications are legitimate

A number of women use compounded medications because they make it possible to obtain hormone combinations that are not readily available in cream form. For example, if a patient wants testosterone as part of a cream of estrogen and progesterone, a compounded product is the only option.

Show me the data

No studies have compared compounded drugs with commercial drugs—and such studies are exceedingly unlikely. Compounding pharmacies have no incentive to conduct or participate in such studies. The pharmaceutical compounding industry is a multibillion-dollar enterprise in this country, and compounded prescription drugs for menopausal conditions are probably the biggest product outside of the oncology arena. Proponents of compounded hormones have a captive audience, so to speak, made up of women who don’t like commercial drug manufacturers or who prefer products that appear to be natural, or both.

The problem is that these women receive no package insert or prescription drug label with their hormones. Warning labels are not required because compounded drugs are not regulated by the FDA. Consumers are basically at the mercy of whatever claims they read on the Internet or in the lay literature, which tends to be written by people who have a financial interest in affiliating with the compounding industry. It’s a very frustrating situation for a lot of people.

Unintended consequences of the WHI

The Women’s Health Initiative (WHI) stirred demand for bioidentical hormones by casting the safety claims for some commercial hormone therapy products in a less than favorable light. That wasn’t the investigators’ intent, of course, and some of the findings of the WHI have since been questioned.

The goal of the WHI was to critically evaluate some of the touted health benefits of commercial hormone therapy prescription drugs, but, by questioning some of these claims, it inadvertently pushed a significant percentage of patients toward compounded prescription drugs—and we have no safety data on them.

No one knows exactly how many women were swayed, but the consensus is that they were, and no one’s been happy about that.

The main problem with the compounded hormones, as I see it, is that women who use them do not receive any written information from the compounding pharmacist about risks and benefits. Nor do they receive the black box warnings on FDA-approved estrogen therapy. I believe women need to be adequately educated about the potential risks and benefits, as well as the lack of efficacy data and quality control, if compounded products are requested. That means it’s up to the prescriber to educate the patient about the potential risks and benefits.

Rosenthal states that symptomatic menopausal women or those who fear breast cancer or heart disease can be considered a vulnerable population: “Patients do not have the background to decipher credible sources from noncredible sources.” False claims present convincing arguments for laypersons. A woman may be vulnerable to unsubstantiated claims by virtue of her symptoms and the anxiety and even depression that they can produce. Without comprehensive education, these women cannot be assumed to be adequately informed.

Let me put it in perspective. If a patient with a history of breast cancer complains about severe vaginal dryness that interferes with her sex life, I might decide to give her the smallest amount of topical estrogen that I can—for example, a dime-sized amount of estrogen to apply to her vulvar area twice a week. This amount of estrogen can’t be detected in her system with current assays. I know that some of it will be systemically absorbed, but it cannot be detected. When the patient buys that commercially prepared cream from the pharmacist, she will receive the same black box warning that comes with all systemic hormones since the WHI. However, if she goes to a compounding pharmacist with a prescription for bioidentical hormone therapy, she will not get the warning, regardless of the ingredients or dosage.

Are compounded bioidenticals ever justified?

OBG MANAGEMENT: According to the FDA, compounding of drug products is justified only when a practitioner finds that an FDA-approved drug does not meet the patient’s needs. Do you think this is ever really the case, given the availability of FDA-approved bioidentical hormone preparations?

DR. PINKERTON: In rare cases, compounding of bioidentical hormones is justified, such as when a patient cannot tolerate an FDA-approved product. The problem is that women have been especially concerned about the safety of hormone therapy since the WHI, and bioidentical hormones have been promoted as being safer than FDA-regulated preparations, despite the lack of evidence of their safety or efficacy in peer-reviewed literature. So many women request them.

In a recent commentary, Boothby and Doering call bioidentical hormone therapy “a panacea that lacks supportive evidence.” They say, “It’s our belief that pharmacists are compounding these with the best intentions, but they are ill informed regarding the lack of scientific underpinning associated with efficacy and safety.”³

OBG MANAGEMENT: Do you ever prescribe bioidentical hormones?

DR. PINKERTON: Yes, but rarely, and primarily for women who can’t tolerate FDA-approved hormones or who, after adequate information and education, refuse FDA-approved hormone therapy.

Is salivary hormone testing informative?

OBG MANAGEMENT: Many clinicians who prescribe bioidentical hormones base the dosage on salivary hormone testing. They claim that this allows them to offer individualized formulations. Is this a reliable claim?

DR. PINKERTON: No, it isn’t. Although compounded bioidentical hormone therapy is often prescribed on the basis of salivary hormone testing, there is no scientific evidence that a correlation exists between a patient’s symptoms and salivary hormones, or that salivary hormone testing reflects what is happening at the tissue level. As Fugh-Berman and Bythrow have observed, this type of testing is often used to convince asymptomatic consumers to use hormones—or symptomatic women to take higher dosages. That practice is likely to lead to adverse events.⁵ The practice also directly contradicts evidence-based guidelines, which recommend that hormone therapy be individualized on the basis of symptoms, not hormone levels.⁶

There are no published studies in the peer-reviewed literature that show that salivary testing is a reliable measure on which to safely and effectively base dosing decisions. Indeed, The Endocrine Society issued a position statement that notes, among other issues, that salivary hormone tests are “inaccurate and should not be considered reliable measures of hormones in the body.”⁷ The American College of Obstetricians and Gynecologists also advises against salivary testing, observing that:

• 1) there is no biologically meaningful relationship between salivary sex steroidal hormone concentrations and free serum hormone concentrations
• 2) there is large within-patient variability in salivary hormone concentrations. Salivary hormone levels vary depending on diet, time of day of testing, the specific hormone being tested, and other variables.³

Do bioidenticals protect against cancer?

OBG MANAGEMENT: Some reports mention the fact that many women believe that bioidentical hormones—specifically, estriol—can reduce their risk of breast and endometrial cancer. Is there any truth behind this belief?

DR. PINKERTON: Estriol is a weak estrogen. There is no evidence that, if it is given at a dosage high enough to relieve symptoms, it is any safer than estradiol.

In regard to endometrial cancer, if the exogenous estrogen—bioidentical or otherwise—is unopposed or inadequately opposed, the risk of endometrial cancer is elevated. The problem is that it is hard to determine whether estrogen is being adequately opposed, particularly when transdermal compounded progesterone is given, because the progesterone molecule is too large to be well-absorbed systemically.⁹

In regard to breast cancer, estriol is a less potent estrogen than estradiol, but it is believed to carry the same risks if it is dosed at effective levels. There is nothing about estriol per se in the peer-reviewed literature that shows that it protects against breast cancer.

The data on risk of breast cancer with estrogen therapy is confusing, with potentially higher risks if estrogen is combined with progestogen. Most of the data we have on estriol come from animals, but a study from 1980 in humans showed that, when older women with breast cancer were treated with estriol, 25% had increased growth of metastases.⁸

How do you monitor use of bioidentical hormones?

OBG MANAGEMENT: When you do prescribe a compounded bioidentical hormone, how do you monitor the patient?

DR. PINKERTON: First, I want to reiterate that I prescribe these hormones after considerable patient education about FDA-approved options and their potential risks. Second, when a patient needs or requests hormone therapy, I recommend conventional therapy. Only when she cannot tolerate or refuses FDA-approved drugs do I consider prescribing compounded bioidentical hormones—which, as I said earlier, are assumed to carry risks identical to those of FDA-approved hormones.

In some cases, I provide gynecologic care for patients who obtain compounded bioidentical hormones from other sources. What I will sometimes do, just to give myself some idea of how much estrogen they are getting, is to measure the peak and trough estradiol and estrone levels. That is, I measure the hormone level within 4 hours of the patient taking the drug to see how high it goes, and again about 12 hours later to see how low it goes. I measure both because estradiol may be peripherally converted to estrone.

Regrettably, we don’t know what to do about the various hormone levels. It isn’t like treating thyroid disorders; we normally dose estrogen therapy based on symptoms.

Who pays?

OBG MANAGEMENT: Who pays for salivary testing and compounded bioidentical hormones? Does health insurance cover them?

DR. PINKERTON: Like other “natural” products, compounded bioidenticals may cost more than their commercially prepared counterparts and often are not covered by insurance. In addition, prescribers may charge more for a “consultation” than do practitioners who accept insurance; they also may recommend salivary testing, which is expensive. Patients can end up paying large sums out of pocket.

As Rosenthal noted, many women do not appear to be concerned about the added costs.² That may be because compounded bioidentical hormone therapy is usually offered to economically advantaged patients.²

Ethical considerations

OBG MANAGEMENT: That raises an important question: What ethical considerations are inherent in the prescribing of compounded bioidenticals?

DR. PINKERTON: The fact that women who are able to pay out of pocket are the primary users of these drugs is one important point. In her analysis of the ethics surrounding bioidentical hormones, Rosenthal noted that the drugs remain “an unequal alternative, and any data collected would not be representative of the overall menopausal community.”²

A critical issue pointed out by Rosenthal is that perimenopausal and menopausal women may be particularly vulnerable to the unsubstantiated claims of purveyors of bio identical hormones. “A substantial number of women seek out bioidentical hormone replacement therapy to restore sexual well-being and functioning, in particular, who may be psychologically more vulnerable,” she writes.²

Another concern arises when the practitioner who prescribes bioidentical hormones also happens to sell them. This poses a potential conflict of interest and “violates professional ethical conduct.”²

OBG MANAGEMENT: Do physicians aggravate the problem when they accede to a patient’s request for compounded hormones?

DR. PINKERTON: Physicians and health-care providers need to stop and educate the patient about the lack of safety and efficacy data, the risks and benefits, and recognize the possibility that she has been influenced by unsubstantiated claims.

OBG Management Senior Editor Janelle Yates contributed to this article.

Hear Dr. Pinkerton discuss this article

The Women’s Health Initiative (WHI) caused a sea change in women’s attitudes toward menopausal hormone therapy and aroused many fears—not always rational—that remain almost palpable today. One study of the aftermath of the WHI found that 70% of women who were taking hormone therapy discontinued it, and 26% of women lost confidence in medical recommendations in general.¹

Into the chaos stepped Suzanne Somers, Michael Platt, and other celebrities, touting the benefits of a new kind of hormone: bioidentical. You don’t have to read Somers’ bestseller, The Sexy Years, to encounter the claims it makes on behalf of bioidenticals; the cover itself makes them clear: Discover the Hormone Connection—The Secret to Fabulous Sex, Great Health and Vitality, for Women and Men. Since publication of the book, the demand for bioidentical hormones has only increased, as women remain fearful about conventional hormone therapy.

Many ObGyns regularly field requests from patients for specially compounded bioidentical regimens. In most cases, the women who ask for these drugs are poorly informed about their risks and willing to pay out of pocket to acquire them. JoAnn V. Pinkerton, MD, sees many of these patients at The Women’s Place Midlife Health Center in Charlottesville, Virginia. OBG Management recently sat down with Dr. Pinkerton to discuss her concerns about the growing ubiquity of compounded bioidentical hormones. In the Q&A that follows, we talk about what “bioidentical” actually means, whether these hormones are ever justified, common misconceptions about them, and other issues.

In a special accompanying commentary, former Food and Drug Administration (FDA) Senior Medical Officer Bruce Patsner, MD, JD, also weighs in on the issue.

What is “bioidentical”?

OBG MANAGEMENT: Let’s start with the basics. What does the word “bioidentical” mean? Is it a legitimate medical term?

DR. PINKERTON: Bioidentical hormones are exogenous hormones that are biochemically similar to those produced endogenously by the body or ovaries. These include estrone, estradiol, estriol, progesterone, testosterone, dehydroepiandrosterone (DHEA), and cortisol. The FDA has approved many prescription products that contain bioidentical hormones. However, the term “bioidentical” is often used to refer to custom-compounded hormones. The major difference between the FDA-approved prescription bioidentical hormone products and custom-compounded products is that the former are regulated by the FDA and tested for purity, potency, efficacy, and safety.

Bioidenticals are not “natural” hormones, although many consumers think they are. In reality, compounded bioidentical hormones and FDA-approved bioidentical hormones all come from the same precursors. They begin as soy products or wild yam and then get converted to the different hormones in a laboratory in Germany before finding their way to the various world markets.

The claim that all bioidentical hormones are bioengineered to contain the same chemical structure as natural female sex hormones is false. As one expert noted, “the term ‘bioidentical’ has become inappropriately synonymous with ‘natural’ or ‘not synthetic’ and should be redefined to correct patient misconceptions.”²

Common misconceptions

OBG MANAGEMENT: What are some of the other false impressions you encounter among patients who ask for bioidenticals?

DR. PINKERTON: That the hormones are safer or more effective than hormone therapy, that they carry no risks, and that they are as well-monitored as FDA-approved products, to name a few. (For more, see “10 erroneous beliefs patients have about compounded hormones”).

OBG MANAGEMENT: Where do these ideas originate?

DR. PINKERTON: They are propagated by self-proclaimed experts and celebrities or by laypersons and physicians who devote the bulk of their time to promoting these hormones, usually at considerable cost to the patient.

OBG MANAGEMENT: What are the risks of compounded bioidentical hormones?

DR. PINKERTON: According to FDA guidance for industry, in the absence of data about these hormones, the risks and benefits should be assumed to be identical to those of FDA-approved hormone therapies, with the caveat that we don’t know from batch to batch what a woman is receiving. However, they are not regulated or monitored by the FDA, so we are lacking testing for purity, potency, efficacy, and safety. When the FDA did analyze compounded bioidentical hormones, a significant percentage (34%) failed one or more standard quality tests.³ In comparison, FDA-approved drugs fail analytical testing at a rate of less than 2%.³

The problems with compounded hormones

BRUCE PATSNER, MD, JD
Dr. Patsner is Research Professor of Law at the University of Houston Law Center in Houston, Tex. He served as Senior Medical Officer at the US Food and Drug Administration (FDA), where he was one of the agency’s experts on pharmacy compounding of prescription hormone drug therapy for the treatment of menopausal conditions.

The FDA has nothing against compounding pharmacies per se. Individualized preparation of a customized medication for a patient, based on a valid prescription, is an essential part of the practice of pharmacy. However, some actors in the pharmacy compounding business have taken the practice to a different level, not just in terms of the volume of business they do, but in the way compounded hormones are advertised and promoted. The courts aren’t necessarily interested in intervening in cases involving high volume alone. And when it comes to unsubstantiated claims of benefit, the FDA has found it difficult to assert jurisdiction over pharmacy compounding in general, making it hard to assert control over the advertising claims these pharmacies make on behalf of compounded drugs.

The result? The FDA has been unable to rein in claims that compounded prescription drugs are safer or better than commercially prepared medications. These drugs are probably as safe and effective as their manufactured counterparts, but there are no data to confirm this assumption.

What’s in a name?

“Bioidentical” isn’t a bona fide term. There is no definition of it in any medical dictionary; it’s just a name the industry cooked up, a catchy one at that. And when bioidenticals are advertised and promoted, the term “natural” is usually in close proximity. Most patients equate the word natural with plant-derived substances that have not been chemically altered. The fact is, many compounded prescription drugs are derived from plants—but they are also chemically altered.

Some applications are legitimate

A number of women use compounded medications because they make it possible to obtain hormone combinations that are not readily available in cream form. For example, if a patient wants testosterone as part of a cream of estrogen and progesterone, a compounded product is the only option.

Show me the data

No studies have compared compounded drugs with commercial drugs—and such studies are exceedingly unlikely. Compounding pharmacies have no incentive to conduct or participate in such studies. The pharmaceutical compounding industry is a multibillion-dollar enterprise in this country, and compounded prescription drugs for menopausal conditions are probably the biggest product outside of the oncology arena. Proponents of compounded hormones have a captive audience, so to speak, made up of women who don’t like commercial drug manufacturers or who prefer products that appear to be natural, or both.

The problem is that these women receive no package insert or prescription drug label with their hormones. Warning labels are not required because compounded drugs are not regulated by the FDA. Consumers are basically at the mercy of whatever claims they read on the Internet or in the lay literature, which tends to be written by people who have a financial interest in affiliating with the compounding industry. It’s a very frustrating situation for a lot of people.

Unintended consequences of the WHI

The Women’s Health Initiative (WHI) stirred demand for bioidentical hormones by casting the safety claims for some commercial hormone therapy products in a less than favorable light. That wasn’t the investigators’ intent, of course, and some of the findings of the WHI have since been questioned.

The goal of the WHI was to critically evaluate some of the touted health benefits of commercial hormone therapy prescription drugs, but, by questioning some of these claims, it inadvertently pushed a significant percentage of patients toward compounded prescription drugs—and we have no safety data on them.

No one knows exactly how many women were swayed, but the consensus is that they were, and no one’s been happy about that.

The main problem with the compounded hormones, as I see it, is that women who use them do not receive any written information from the compounding pharmacist about risks and benefits. Nor do they receive the black box warnings on FDA-approved estrogen therapy. I believe women need to be adequately educated about the potential risks and benefits, as well as the lack of efficacy data and quality control, if compounded products are requested. That means it’s up to the prescriber to educate the patient about the potential risks and benefits.

Rosenthal states that symptomatic menopausal women or those who fear breast cancer or heart disease can be considered a vulnerable population: “Patients do not have the background to decipher credible sources from noncredible sources.” False claims present convincing arguments for laypersons. A woman may be vulnerable to unsubstantiated claims by virtue of her symptoms and the anxiety and even depression that they can produce. Without comprehensive education, these women cannot be assumed to be adequately informed.

Let me put it in perspective. If a patient with a history of breast cancer complains about severe vaginal dryness that interferes with her sex life, I might decide to give her the smallest amount of topical estrogen that I can—for example, a dime-sized amount of estrogen to apply to her vulvar area twice a week. This amount of estrogen can’t be detected in her system with current assays. I know that some of it will be systemically absorbed, but it cannot be detected. When the patient buys that commercially prepared cream from the pharmacist, she will receive the same black box warning that comes with all systemic hormones since the WHI. However, if she goes to a compounding pharmacist with a prescription for bioidentical hormone therapy, she will not get the warning, regardless of the ingredients or dosage.

Are compounded bioidenticals ever justified?

OBG MANAGEMENT: According to the FDA, compounding of drug products is justified only when a practitioner finds that an FDA-approved drug does not meet the patient’s needs. Do you think this is ever really the case, given the availability of FDA-approved bioidentical hormone preparations?

DR. PINKERTON: In rare cases, compounding of bioidentical hormones is justified, such as when a patient cannot tolerate an FDA-approved product. The problem is that women have been especially concerned about the safety of hormone therapy since the WHI, and bioidentical hormones have been promoted as being safer than FDA-regulated preparations, despite the lack of evidence of their safety or efficacy in peer-reviewed literature. So many women request them.

In a recent commentary, Boothby and Doering call bioidentical hormone therapy “a panacea that lacks supportive evidence.” They say, “It’s our belief that pharmacists are compounding these with the best intentions, but they are ill informed regarding the lack of scientific underpinning associated with efficacy and safety.”³

OBG MANAGEMENT: Do you ever prescribe bioidentical hormones?

DR. PINKERTON: Yes, but rarely, and primarily for women who can’t tolerate FDA-approved hormones or who, after adequate information and education, refuse FDA-approved hormone therapy.

Is salivary hormone testing informative?

OBG MANAGEMENT: Many clinicians who prescribe bioidentical hormones base the dosage on salivary hormone testing. They claim that this allows them to offer individualized formulations. Is this a reliable claim?

DR. PINKERTON: No, it isn’t. Although compounded bioidentical hormone therapy is often prescribed on the basis of salivary hormone testing, there is no scientific evidence that a correlation exists between a patient’s symptoms and salivary hormones, or that salivary hormone testing reflects what is happening at the tissue level. As Fugh-Berman and Bythrow have observed, this type of testing is often used to convince asymptomatic consumers to use hormones—or symptomatic women to take higher dosages. That practice is likely to lead to adverse events.⁵ The practice also directly contradicts evidence-based guidelines, which recommend that hormone therapy be individualized on the basis of symptoms, not hormone levels.⁶

There are no published studies in the peer-reviewed literature that show that salivary testing is a reliable measure on which to safely and effectively base dosing decisions. Indeed, The Endocrine Society issued a position statement that notes, among other issues, that salivary hormone tests are “inaccurate and should not be considered reliable measures of hormones in the body.”⁷ The American College of Obstetricians and Gynecologists also advises against salivary testing, observing that:

• 1) there is no biologically meaningful relationship between salivary sex steroidal hormone concentrations and free serum hormone concentrations
• 2) there is large within-patient variability in salivary hormone concentrations. Salivary hormone levels vary depending on diet, time of day of testing, the specific hormone being tested, and other variables.³

Do bioidenticals protect against cancer?

OBG MANAGEMENT: Some reports mention the fact that many women believe that bioidentical hormones—specifically, estriol—can reduce their risk of breast and endometrial cancer. Is there any truth behind this belief?

DR. PINKERTON: Estriol is a weak estrogen. There is no evidence that, if it is given at a dosage high enough to relieve symptoms, it is any safer than estradiol.

In regard to endometrial cancer, if the exogenous estrogen—bioidentical or otherwise—is unopposed or inadequately opposed, the risk of endometrial cancer is elevated. The problem is that it is hard to determine whether estrogen is being adequately opposed, particularly when transdermal compounded progesterone is given, because the progesterone molecule is too large to be well-absorbed systemically.⁹

In regard to breast cancer, estriol is a less potent estrogen than estradiol, but it is believed to carry the same risks if it is dosed at effective levels. There is nothing about estriol per se in the peer-reviewed literature that shows that it protects against breast cancer.

The data on risk of breast cancer with estrogen therapy is confusing, with potentially higher risks if estrogen is combined with progestogen. Most of the data we have on estriol come from animals, but a study from 1980 in humans showed that, when older women with breast cancer were treated with estriol, 25% had increased growth of metastases.⁸

How do you monitor use of bioidentical hormones?

OBG MANAGEMENT: When you do prescribe a compounded bioidentical hormone, how do you monitor the patient?

DR. PINKERTON: First, I want to reiterate that I prescribe these hormones after considerable patient education about FDA-approved options and their potential risks. Second, when a patient needs or requests hormone therapy, I recommend conventional therapy. Only when she cannot tolerate or refuses FDA-approved drugs do I consider prescribing compounded bioidentical hormones—which, as I said earlier, are assumed to carry risks identical to those of FDA-approved hormones.

In some cases, I provide gynecologic care for patients who obtain compounded bioidentical hormones from other sources. What I will sometimes do, just to give myself some idea of how much estrogen they are getting, is to measure the peak and trough estradiol and estrone levels. That is, I measure the hormone level within 4 hours of the patient taking the drug to see how high it goes, and again about 12 hours later to see how low it goes. I measure both because estradiol may be peripherally converted to estrone.

Regrettably, we don’t know what to do about the various hormone levels. It isn’t like treating thyroid disorders; we normally dose estrogen therapy based on symptoms.

Who pays?

OBG MANAGEMENT: Who pays for salivary testing and compounded bioidentical hormones? Does health insurance cover them?

DR. PINKERTON: Like other “natural” products, compounded bioidenticals may cost more than their commercially prepared counterparts and often are not covered by insurance. In addition, prescribers may charge more for a “consultation” than do practitioners who accept insurance; they also may recommend salivary testing, which is expensive. Patients can end up paying large sums out of pocket.

As Rosenthal noted, many women do not appear to be concerned about the added costs.² That may be because compounded bioidentical hormone therapy is usually offered to economically advantaged patients.²

Ethical considerations

OBG MANAGEMENT: That raises an important question: What ethical considerations are inherent in the prescribing of compounded bioidenticals?

DR. PINKERTON: The fact that women who are able to pay out of pocket are the primary users of these drugs is one important point. In her analysis of the ethics surrounding bioidentical hormones, Rosenthal noted that the drugs remain “an unequal alternative, and any data collected would not be representative of the overall menopausal community.”²

A critical issue pointed out by Rosenthal is that perimenopausal and menopausal women may be particularly vulnerable to the unsubstantiated claims of purveyors of bio identical hormones. “A substantial number of women seek out bioidentical hormone replacement therapy to restore sexual well-being and functioning, in particular, who may be psychologically more vulnerable,” she writes.²

Another concern arises when the practitioner who prescribes bioidentical hormones also happens to sell them. This poses a potential conflict of interest and “violates professional ethical conduct.”²

OBG MANAGEMENT: Do physicians aggravate the problem when they accede to a patient’s request for compounded hormones?

DR. PINKERTON: Physicians and health-care providers need to stop and educate the patient about the lack of safety and efficacy data, the risks and benefits, and recognize the possibility that she has been influenced by unsubstantiated claims.

OBG Management Senior Editor Janelle Yates contributed to this article.

Hear Dr. Pinkerton discuss this article

The Women’s Health Initiative (WHI) caused a sea change in women’s attitudes toward menopausal hormone therapy and aroused many fears—not always rational—that remain almost palpable today. One study of the aftermath of the WHI found that 70% of women who were taking hormone therapy discontinued it, and 26% of women lost confidence in medical recommendations in general.¹

Into the chaos stepped Suzanne Somers, Michael Platt, and other celebrities, touting the benefits of a new kind of hormone: bioidentical. You don’t have to read Somers’ bestseller, The Sexy Years, to encounter the claims it makes on behalf of bioidenticals; the cover itself makes them clear: Discover the Hormone Connection—The Secret to Fabulous Sex, Great Health and Vitality, for Women and Men. Since publication of the book, the demand for bioidentical hormones has only increased, as women remain fearful about conventional hormone therapy.

Many ObGyns regularly field requests from patients for specially compounded bioidentical regimens. In most cases, the women who ask for these drugs are poorly informed about their risks and willing to pay out of pocket to acquire them. JoAnn V. Pinkerton, MD, sees many of these patients at The Women’s Place Midlife Health Center in Charlottesville, Virginia. OBG Management recently sat down with Dr. Pinkerton to discuss her concerns about the growing ubiquity of compounded bioidentical hormones. In the Q&A that follows, we talk about what “bioidentical” actually means, whether these hormones are ever justified, common misconceptions about them, and other issues.

In a special accompanying commentary, former Food and Drug Administration (FDA) Senior Medical Officer Bruce Patsner, MD, JD, also weighs in on the issue.

What is “bioidentical”?

OBG MANAGEMENT: Let’s start with the basics. What does the word “bioidentical” mean? Is it a legitimate medical term?

DR. PINKERTON: Bioidentical hormones are exogenous hormones that are biochemically similar to those produced endogenously by the body or ovaries. These include estrone, estradiol, estriol, progesterone, testosterone, dehydroepiandrosterone (DHEA), and cortisol. The FDA has approved many prescription products that contain bioidentical hormones. However, the term “bioidentical” is often used to refer to custom-compounded hormones. The major difference between the FDA-approved prescription bioidentical hormone products and custom-compounded products is that the former are regulated by the FDA and tested for purity, potency, efficacy, and safety.

Bioidenticals are not “natural” hormones, although many consumers think they are. In reality, compounded bioidentical hormones and FDA-approved bioidentical hormones all come from the same precursors. They begin as soy products or wild yam and then get converted to the different hormones in a laboratory in Germany before finding their way to the various world markets.

The claim that all bioidentical hormones are bioengineered to contain the same chemical structure as natural female sex hormones is false. As one expert noted, “the term ‘bioidentical’ has become inappropriately synonymous with ‘natural’ or ‘not synthetic’ and should be redefined to correct patient misconceptions.”²

Common misconceptions

OBG MANAGEMENT: What are some of the other false impressions you encounter among patients who ask for bioidenticals?

DR. PINKERTON: That the hormones are safer or more effective than hormone therapy, that they carry no risks, and that they are as well-monitored as FDA-approved products, to name a few. (For more, see “10 erroneous beliefs patients have about compounded hormones”).

OBG MANAGEMENT: Where do these ideas originate?

DR. PINKERTON: They are propagated by self-proclaimed experts and celebrities or by laypersons and physicians who devote the bulk of their time to promoting these hormones, usually at considerable cost to the patient.

OBG MANAGEMENT: What are the risks of compounded bioidentical hormones?

DR. PINKERTON: According to FDA guidance for industry, in the absence of data about these hormones, the risks and benefits should be assumed to be identical to those of FDA-approved hormone therapies, with the caveat that we don’t know from batch to batch what a woman is receiving. However, they are not regulated or monitored by the FDA, so we are lacking testing for purity, potency, efficacy, and safety. When the FDA did analyze compounded bioidentical hormones, a significant percentage (34%) failed one or more standard quality tests.³ In comparison, FDA-approved drugs fail analytical testing at a rate of less than 2%.³

The problems with compounded hormones

BRUCE PATSNER, MD, JD
Dr. Patsner is Research Professor of Law at the University of Houston Law Center in Houston, Tex. He served as Senior Medical Officer at the US Food and Drug Administration (FDA), where he was one of the agency’s experts on pharmacy compounding of prescription hormone drug therapy for the treatment of menopausal conditions.

The FDA has nothing against compounding pharmacies per se. Individualized preparation of a customized medication for a patient, based on a valid prescription, is an essential part of the practice of pharmacy. However, some actors in the pharmacy compounding business have taken the practice to a different level, not just in terms of the volume of business they do, but in the way compounded hormones are advertised and promoted. The courts aren’t necessarily interested in intervening in cases involving high volume alone. And when it comes to unsubstantiated claims of benefit, the FDA has found it difficult to assert jurisdiction over pharmacy compounding in general, making it hard to assert control over the advertising claims these pharmacies make on behalf of compounded drugs.

The result? The FDA has been unable to rein in claims that compounded prescription drugs are safer or better than commercially prepared medications. These drugs are probably as safe and effective as their manufactured counterparts, but there are no data to confirm this assumption.

What’s in a name?

“Bioidentical” isn’t a bona fide term. There is no definition of it in any medical dictionary; it’s just a name the industry cooked up, a catchy one at that. And when bioidenticals are advertised and promoted, the term “natural” is usually in close proximity. Most patients equate the word natural with plant-derived substances that have not been chemically altered. The fact is, many compounded prescription drugs are derived from plants—but they are also chemically altered.

Some applications are legitimate

A number of women use compounded medications because they make it possible to obtain hormone combinations that are not readily available in cream form. For example, if a patient wants testosterone as part of a cream of estrogen and progesterone, a compounded product is the only option.

Show me the data

No studies have compared compounded drugs with commercial drugs—and such studies are exceedingly unlikely. Compounding pharmacies have no incentive to conduct or participate in such studies. The pharmaceutical compounding industry is a multibillion-dollar enterprise in this country, and compounded prescription drugs for menopausal conditions are probably the biggest product outside of the oncology arena. Proponents of compounded hormones have a captive audience, so to speak, made up of women who don’t like commercial drug manufacturers or who prefer products that appear to be natural, or both.

The problem is that these women receive no package insert or prescription drug label with their hormones. Warning labels are not required because compounded drugs are not regulated by the FDA. Consumers are basically at the mercy of whatever claims they read on the Internet or in the lay literature, which tends to be written by people who have a financial interest in affiliating with the compounding industry. It’s a very frustrating situation for a lot of people.

Unintended consequences of the WHI

The Women’s Health Initiative (WHI) stirred demand for bioidentical hormones by casting the safety claims for some commercial hormone therapy products in a less than favorable light. That wasn’t the investigators’ intent, of course, and some of the findings of the WHI have since been questioned.

The goal of the WHI was to critically evaluate some of the touted health benefits of commercial hormone therapy prescription drugs, but, by questioning some of these claims, it inadvertently pushed a significant percentage of patients toward compounded prescription drugs—and we have no safety data on them.

No one knows exactly how many women were swayed, but the consensus is that they were, and no one’s been happy about that.

The main problem with the compounded hormones, as I see it, is that women who use them do not receive any written information from the compounding pharmacist about risks and benefits. Nor do they receive the black box warnings on FDA-approved estrogen therapy. I believe women need to be adequately educated about the potential risks and benefits, as well as the lack of efficacy data and quality control, if compounded products are requested. That means it’s up to the prescriber to educate the patient about the potential risks and benefits.

Rosenthal states that symptomatic menopausal women or those who fear breast cancer or heart disease can be considered a vulnerable population: “Patients do not have the background to decipher credible sources from noncredible sources.” False claims present convincing arguments for laypersons. A woman may be vulnerable to unsubstantiated claims by virtue of her symptoms and the anxiety and even depression that they can produce. Without comprehensive education, these women cannot be assumed to be adequately informed.

Let me put it in perspective. If a patient with a history of breast cancer complains about severe vaginal dryness that interferes with her sex life, I might decide to give her the smallest amount of topical estrogen that I can—for example, a dime-sized amount of estrogen to apply to her vulvar area twice a week. This amount of estrogen can’t be detected in her system with current assays. I know that some of it will be systemically absorbed, but it cannot be detected. When the patient buys that commercially prepared cream from the pharmacist, she will receive the same black box warning that comes with all systemic hormones since the WHI. However, if she goes to a compounding pharmacist with a prescription for bioidentical hormone therapy, she will not get the warning, regardless of the ingredients or dosage.

Are compounded bioidenticals ever justified?

OBG MANAGEMENT: According to the FDA, compounding of drug products is justified only when a practitioner finds that an FDA-approved drug does not meet the patient’s needs. Do you think this is ever really the case, given the availability of FDA-approved bioidentical hormone preparations?

DR. PINKERTON: In rare cases, compounding of bioidentical hormones is justified, such as when a patient cannot tolerate an FDA-approved product. The problem is that women have been especially concerned about the safety of hormone therapy since the WHI, and bioidentical hormones have been promoted as being safer than FDA-regulated preparations, despite the lack of evidence of their safety or efficacy in peer-reviewed literature. So many women request them.

In a recent commentary, Boothby and Doering call bioidentical hormone therapy “a panacea that lacks supportive evidence.” They say, “It’s our belief that pharmacists are compounding these with the best intentions, but they are ill informed regarding the lack of scientific underpinning associated with efficacy and safety.”³

OBG MANAGEMENT: Do you ever prescribe bioidentical hormones?

DR. PINKERTON: Yes, but rarely, and primarily for women who can’t tolerate FDA-approved hormones or who, after adequate information and education, refuse FDA-approved hormone therapy.

Is salivary hormone testing informative?

OBG MANAGEMENT: Many clinicians who prescribe bioidentical hormones base the dosage on salivary hormone testing. They claim that this allows them to offer individualized formulations. Is this a reliable claim?

DR. PINKERTON: No, it isn’t. Although compounded bioidentical hormone therapy is often prescribed on the basis of salivary hormone testing, there is no scientific evidence that a correlation exists between a patient’s symptoms and salivary hormones, or that salivary hormone testing reflects what is happening at the tissue level. As Fugh-Berman and Bythrow have observed, this type of testing is often used to convince asymptomatic consumers to use hormones—or symptomatic women to take higher dosages. That practice is likely to lead to adverse events.⁵ The practice also directly contradicts evidence-based guidelines, which recommend that hormone therapy be individualized on the basis of symptoms, not hormone levels.⁶

There are no published studies in the peer-reviewed literature that show that salivary testing is a reliable measure on which to safely and effectively base dosing decisions. Indeed, The Endocrine Society issued a position statement that notes, among other issues, that salivary hormone tests are “inaccurate and should not be considered reliable measures of hormones in the body.”⁷ The American College of Obstetricians and Gynecologists also advises against salivary testing, observing that:

• 1) there is no biologically meaningful relationship between salivary sex steroidal hormone concentrations and free serum hormone concentrations
• 2) there is large within-patient variability in salivary hormone concentrations. Salivary hormone levels vary depending on diet, time of day of testing, the specific hormone being tested, and other variables.³

Do bioidenticals protect against cancer?

OBG MANAGEMENT: Some reports mention the fact that many women believe that bioidentical hormones—specifically, estriol—can reduce their risk of breast and endometrial cancer. Is there any truth behind this belief?

DR. PINKERTON: Estriol is a weak estrogen. There is no evidence that, if it is given at a dosage high enough to relieve symptoms, it is any safer than estradiol.

In regard to endometrial cancer, if the exogenous estrogen—bioidentical or otherwise—is unopposed or inadequately opposed, the risk of endometrial cancer is elevated. The problem is that it is hard to determine whether estrogen is being adequately opposed, particularly when transdermal compounded progesterone is given, because the progesterone molecule is too large to be well-absorbed systemically.⁹

In regard to breast cancer, estriol is a less potent estrogen than estradiol, but it is believed to carry the same risks if it is dosed at effective levels. There is nothing about estriol per se in the peer-reviewed literature that shows that it protects against breast cancer.

The data on risk of breast cancer with estrogen therapy is confusing, with potentially higher risks if estrogen is combined with progestogen. Most of the data we have on estriol come from animals, but a study from 1980 in humans showed that, when older women with breast cancer were treated with estriol, 25% had increased growth of metastases.⁸

How do you monitor use of bioidentical hormones?

OBG MANAGEMENT: When you do prescribe a compounded bioidentical hormone, how do you monitor the patient?

DR. PINKERTON: First, I want to reiterate that I prescribe these hormones after considerable patient education about FDA-approved options and their potential risks. Second, when a patient needs or requests hormone therapy, I recommend conventional therapy. Only when she cannot tolerate or refuses FDA-approved drugs do I consider prescribing compounded bioidentical hormones—which, as I said earlier, are assumed to carry risks identical to those of FDA-approved hormones.

In some cases, I provide gynecologic care for patients who obtain compounded bioidentical hormones from other sources. What I will sometimes do, just to give myself some idea of how much estrogen they are getting, is to measure the peak and trough estradiol and estrone levels. That is, I measure the hormone level within 4 hours of the patient taking the drug to see how high it goes, and again about 12 hours later to see how low it goes. I measure both because estradiol may be peripherally converted to estrone.

Regrettably, we don’t know what to do about the various hormone levels. It isn’t like treating thyroid disorders; we normally dose estrogen therapy based on symptoms.

Who pays?

OBG MANAGEMENT: Who pays for salivary testing and compounded bioidentical hormones? Does health insurance cover them?

DR. PINKERTON: Like other “natural” products, compounded bioidenticals may cost more than their commercially prepared counterparts and often are not covered by insurance. In addition, prescribers may charge more for a “consultation” than do practitioners who accept insurance; they also may recommend salivary testing, which is expensive. Patients can end up paying large sums out of pocket.

As Rosenthal noted, many women do not appear to be concerned about the added costs.² That may be because compounded bioidentical hormone therapy is usually offered to economically advantaged patients.²

Ethical considerations

OBG MANAGEMENT: That raises an important question: What ethical considerations are inherent in the prescribing of compounded bioidenticals?

DR. PINKERTON: The fact that women who are able to pay out of pocket are the primary users of these drugs is one important point. In her analysis of the ethics surrounding bioidentical hormones, Rosenthal noted that the drugs remain “an unequal alternative, and any data collected would not be representative of the overall menopausal community.”²

A critical issue pointed out by Rosenthal is that perimenopausal and menopausal women may be particularly vulnerable to the unsubstantiated claims of purveyors of bio identical hormones. “A substantial number of women seek out bioidentical hormone replacement therapy to restore sexual well-being and functioning, in particular, who may be psychologically more vulnerable,” she writes.²

Another concern arises when the practitioner who prescribes bioidentical hormones also happens to sell them. This poses a potential conflict of interest and “violates professional ethical conduct.”²

OBG MANAGEMENT: Do physicians aggravate the problem when they accede to a patient’s request for compounded hormones?

DR. PINKERTON: Physicians and health-care providers need to stop and educate the patient about the lack of safety and efficacy data, the risks and benefits, and recognize the possibility that she has been influenced by unsubstantiated claims.

Population-based screening for carriers of genetic diseases and advances in neonatal and pediatric genetic testing have resulted in more and more couples identified as at-risk for inherited disorders. Increasingly, women in these couples ask their ObGyn about their options for future pregnancies.

For some women, genetic testing of a pregnancy as early as possible—even before implantation—is desirable. In vitro fertilization affords such direct access to the genetic material of either gametes before fertilization (i.e., polar-body biopsy) or blastomeres once fertilization has occurred (blastomere biopsy). Complex genetic analysis of these single cells is now possible. Because polar-body biopsy is restricted to testing for maternal disease, blastomere biopsy has gained favor as the method of choice for genetic testing of preimplantation pregnancies.

The duality of genetic testing

Regardless of what genetic material is tested, preimplantation genetic testing encompasses two distinct categories: preimplantation genetic diagnosis, or PGD, and preimplantation genetic screening, or PGS.

What is PGD?

Here, testing is confined to women at risk of an offspring with an identified genetic abnormality. These women, or their partner, typically carry a gene mutation that, alone or in combination with another mutation in the same gene, would result in an identifiable outcome in their child (for example, autosomal-recessive, autosomal-dominant, and X-linked disorders).

PGD, by definition, also includes testing of women, or their partner, who possess a balanced chromosome rearrangement (translocation, inversion). Offspring of carriers of balanced chromosome rearrangements are at increased risk of particular genetic abnormalities, as a result of unbalanced segregation of chromosomes involved in their rearrangement.

How does PGS differ from PGD?

Screening, in contrast, focuses analysis on offspring of women who are theoretically at increased risk of a genetic abnormality based on their age or reproductive history, not on their genetic makeup. PGS looks specifically for chromosomal content, and is based on the premise that decreasing the rate of aneuploidy among the conceptions of women 1) of advanced maternal age, 2) who experience habitual miscarriage, or 3) who have failed multiple cycles of in vitro fertilization (IVF) would increase the rate of implantation and, ultimately, the live birth rate.

The articles below, beginning with a committee opinion from the American Society for Reproductive Medicine (ASRM), address the following:

• evidence in support of PGD for genetic disease
  
• caution about using PGS, in its current format, for aneuploidy screening.
  

PGD can reduce the risk of a child with a specific genetic abnormality carried by one or both parents

Practice Committee of the Society for Assisted Reproductive Technology; Practice Committee of the American Society for Reproductive Medicine. Preimplantation genetic testing: a Practice Committee opinion. Fertil Steril. 2007;88:1497–1504.

A gene mutation carried by one or both parents can increase the risk that their offspring will be affected with an inherited condition. Common examples include autosomal-recessive disorders such as cystic fibrosis; autosomal-dominant disorders such as neurofibromatosis; and X-linked disorders such as hemophilia A.

Recently, human leukocyte antigens (HLA) have been assessed in conjunction with testing for specific genetic diseases, such as Fanconi anemia. In these settings, the intent is to recognize not only the blastomeres that are free of Fanconi anemia, but also those that are potential HLA matches and, therefore, potential donors for an (older) affected sibling.

PGD has been extended to women, or their partner, who possess a gene mutation that places them at increased risk of cancer (such as BRCA-1) and who wish to avoid transmitting that risk-conferring gene to their offspring.

For these diseases, and for many others, knowledge of the specific genetic mutation enables similar molecular testing to be accomplished on a single cell, such as a blastomere.

Technical concerns of testing must be part
of the physician–patient discussion

Typically, PGD analysis is initiated by polymerase chain reaction (PCR) of DNA content extracted from the single cell. This is followed by application of mutation-appropriate molecular technology. Given 1) the short time in which these PGD results are needed (often, 24 to 48 hours) and 2) the limited amount of genetic material available for analysis, technical restraints on testing are recognized:

• Extraneous DNA contamination remains a problem with molecular technology, despite application of intracytoplasmic sperm injection
  
• Only partial amplification of the allele may occur, or allele “drop-out” may be present; both of these phenomena can cause false-negative results
  
• Error can occur dually: 1) Presumably unaffected embryos that are, indeed, affected are transferred and 2) actually normal embryos that have been interpreted incorrectly as abnormal are discarded
  
• The rate of misdiagnosis (false-negative results) ranges from 2% (with autosomal-recessive disorders) to 10% (with autosomal-dominant disorders), although this rate can be lessened with the use of linked markers.
  

PGD for investigating balanced chromosome rearrangements

These rearrangements represent another type of genetic abnormality in which PGD can reduce the likelihood of a conception that carries a specific genetic abnormality.

When one parent carries a balanced chromosome translocation, fluorescence in-situ hybridization (FISH) can be applied to assess the segregation of at-risk chromosomes in a single blastomere cell. In this technique, fluorescence-labeled DNA probes, selected for specificity to the translocation in question, are applied to the single cell fixed on a glass slide. Copies of the DNA segment and, by inference, the chromosomal segment in question are assessed by quantification of the sites of positive fluorescence.

Because translocation carriers are, theoretically, at high risk of transmission of an unbalanced segregant to the blastomere, as many as 10 blastomeres will often be screened until one or two are deemed normal for the FISH probes in question. When implantation does succeed after FISH analysis for a chromosome rearrangement, however, the pregnancy loss rate is lower and the likelihood of a live birth is higher.

Again, in-depth consultation is needed before PGD

Whether PGD is planned for investigating a single-gene disorder or a chromosome translocation, detailed consultation with the woman or the couple is important. This effort should include not only genetic counseling about inheritance, the natural history of the disorder in question, and other options for avoiding the transmission of the disorder—in addition, additional time should be spent describing:

• risks associated with IVF procedures and embryo biopsy (and with extended culture, if needed)
  
• technical limitations of the particular testing that is being considered
  
• options for prenatal testing during a pregnancy
  
• the possibility that embryos suitable for transfer will not be found (and that, potentially, erroneously tested normal embryos will not be transferred)
  
• disposition of embryos in which test results are inconclusive.
  

PGS for women at increased risk of aneuploidy isn’t supported by evidence; consider it investigational

Mastenbroek S, Twisk M, van Echten-Arends J, et al. In vitro fertilization with preimplantation genetic screening. N Engl J Med. 2007;357:9–17.

Mersereau JE, Pergament E, Zhang X, Milad MP. Preimplantation genetic screening to improve in vitro fertilization pregnancy rates: a prospective randomized controlled trial. Fertil Steril. 2008;90:1287–1289.

Aneuploidy contributes to pregnancy loss among women as they become older. Theoretically, avoiding aneuploid pregnancy among embryos transferred during IVF cycles—in older women and in women experiencing multiple pregnancy losses and failed IVF cycles—was expected to increase the implantation rate and decrease the rate of pregnancy loss.

This hypothesis was supported, at first, by observational trials. But at least one randomized study, by Staessen and colleagues,¹ failed to demonstrate that PGS is beneficial in women of advanced maternal age.

Now, a large multicenter, randomized, double-blind, controlled trial conducted by Mastenbroek and co-workers provides further evidence that PGS does not increase the rate of pregnancy and, in fact, significantly reduces that rate among women of advanced maternal age.

The Mastenbroek study compared outcomes among 206 women who had PGS and 202 women who did not. Both groups were matched for maternal age older than 35 years. Blastomeres were analyzed for eight chromosomes, including those known to be highly associated with miscarriage (1, 16, 17, 13, 18, and 21; X and Y).

Among women who underwent PGS, 25% had an ongoing pregnancy of at least 12 weeks’ gestation, compared with 37% of unscreened women. A similar higher rate of live birth was seen among unscreened women (35%, versus 24% in the PGS group).

Mastenbroek’s results are comparable to what was reported from an earlier randomized trial of PGS,¹ in which the implantation rate as the primary outcome among women who had PGS and among controls was not significantly different. Contributors to 1) the lack of success of PGS and 2) the apparent detriment of PGS to the ongoing pregnancy rate include:

• potential for damage to the embryo at biopsy
  
• limitations imposed by FISH technology on the number of probes that can be accurately assessed technically
  
• a growing knowledge that a significant percentage of embryos are chromosomal mosaics at this stage—a phenomenon that likely results in nontransfer of embryos that have the potential for developing karyotypically normally.
  

Does PGS improve outcomes?

More recently, Mersereau and colleagues reported pilot results from a prospective, randomized, controlled trial that assessed whether PGS could improve pregnancy outcomes. Here, selection of infertile women for the study was not restricted to poor prognosis categories, such as advanced maternal age and recurrent pregnancy loss.

Using the live birth rate as the outcome measure, PGS for seven chromosomes was determined not to be associated with a significantly increased live birth rate among screened pregnancies. Sample sizes had been calculated to establish, with significance, a 50% increase in live births—from 30% in the control (unscreened) population to 45% in the screened population. Secondary endpoints, such as the implantation rate and pregnancy loss, also did not differ significantly between the PGS cases and controls.

Again, technical difficulties of two-blastomere biopsy, with its potential for embryo damage, and the presence of underlying embryo mosaicism represent possible barriers to improving the live birth rate when utilizing PGS.

Technical limitations may be one of the largest obstacles
to applying PGS

Practice Committee of the Society for Assisted Reproductive Technology; Practice Committee of the American Society for Reproductive Medicine. Preimplantation genetic testing: a Practice Committee opinion. Fertil Steril. 2007;88:1497–1504.

FISH probes can be chosen to reflect the nature of a given patient’s risk (advanced maternal age, recurrent pregnancy loss) when performing PGS, but the technique itself is limited by the number of probe sites that can be interpreted accurately at one time. Typically, analysis of more than five chromosomes requires two cycles of hybridization, with their associated time requirement and potential for degradation of the single cell.

Alternatively, advances in the analysis of all 23 chromosomes through comparative genomic hybridization may, ultimately, provide an avenue for applying PGS. At the moment, time limitations prohibit comparative genomic hybridization without embryo cryopreservation. Further investigation of other technical limitations, such as the high rate of mosaicism, has revealed that, when two cells are examined and found to be karyotypically discordant, further analysis of the entire embryo will reveal that more than 50% of embryos are, in fact, euploid—that is, chromosomally normal. Random biopsy of the abnormal cell solely would relegate the embryo to nontransfer, despite the predominance of an underlying euploid state.

Understanding of the potential that embryos have to self-correct early mosaicism is growing; we now know that almost one half of embryos identified as aneuploid at cleavage stage correct to euploid if they survive to blastocyst stage. A karyotypic abnormality in a single cell from a day-3 embryo does not always signal an abnormal embryo.

ASRM does not support PGS to improve the live birth rate

This determination by ASRM is based on available evidence about advanced maternal age, recurrent pregnancy loss, recurrent implantation failure, and recurrent aneuploidy loss:

• In women of advanced maternal age, many day-3 embryos display aneuploidy when studied by FISH. In theory, exclusion of these embryos for transfer should improve implantation and live birth rates, but evidence does not support that premise.
  
• Because almost 70% of spontaneous pregnancy loss is caused by a karyotypic abnormality, and women with karyotypically recurrent pregnancy loss are more likely to experience subsequent loss with karyotype abnormalities, the premise of preimplantation screening for aneuploidy also appeared to be well founded. Studies at this time are limited to retrospective series, without randomized controlled trials published.
  
• Among women who experience repeated implantation failure, a finding of more than 50% abnormal embryos isn’t uncommon, yet several studies have not supported an increased implantation rate or live birth rate after PGS.
  

A literature review of PGS calls its introduction “premature”

Gleicher N, Weghofer A, Barad D. Preimplantation genetic screening: “established” and ready for prime time? Fertil Steril. 2008;89:780–788.

After ASRM recognized PGD as an established technique in a 2001 committee opinion, extension of this status to PGS was inadvertently assumed. But PGS is a different testing modality—with different indications, risk/benefit profiles, and efficacy than PGD.

Today, FISH probes are utilized for PGS; the false-negative rate of FISH appears to be driven by the technical constraints of the technology. Potentially increasing the false-negative rate are inadequate hybridization and the use of increasing numbers of probes and hybridization cycles.

Conversely, the false-positive rate—the number of embryos not transferred that are, in fact, chromosomally normal—varies markedly from one study to another, and may be as high as 20% when discarded embryos are more completely assessed.

Similarly, laboratories utilize different methods of obtaining the genetic material. These methods range from biopsy of polar bodies to single-cell blastomere and routine two-cell blastomere biopsy—and, more recently, to blastocyst biopsy. The impact of these various embryo manipulations has yet to be fully considered. Whether biopsy affects the embryo has received little attention.

In fact, embryos that are of poor quality before biopsy—such as those found in women of advanced maternal age—may be more susceptible to the effects of biopsy. The outcome with such embryos may be of even greater detriment to the implantation rate (as discussed in regard to the Mastenbroek study earlier in this article).

The logic of performing PGS for aneuploidy in women of advanced maternal age was reasonable. But this group of women—in whom ovarian reserve is diminished, who respond poorly to ovulation induction, thereby limiting the total number of embryos for analysis and the poorer quality embryos possibly further impaired by the biopsy itself—represent the population that may be least amenable to PGS.

A further observation about PGS in women who have experienced recurrent pregnancy loss or IVF failure: Any impairment of embryos that is a consequence of the method of biopsy may further undermine the generally unsupportive results of PGS that have been documented in these patients.

Consensus on performing PGS

An assessment of European studies and practices reveals similar concerns voiced by the European Society for Human Reproduction and Embryology (ESHRE) PGD Consortium Steering Committee. The committee recently asserted a comparable opinion about “the insufficient data that demonstrate PGS is indeed a cost-effective alternative for standard IVF.”² Gleicher and colleagues, in their review of the literature, conclude that the indications for PGS are currently undefined and, as such, screening should be considered experimental.

Gleicher’s sentiments echo the recommendations of ASRM that, when PGS is considered,

• patients undergo counseling about its limitations, risk of error, and lack of evidence that it improves the live-birth rate
  
• available evidence does not support improvement in the live birth rate in women of advanced maternal age, who have failed previous implantation, who have experienced recurrent pregnancy loss, or who have experienced recurrent pregnancy loss specifically related to aneuploidy
  
• decisions about management should not be based on aneuploidy results of prior PGS cycles for a woman who has experienced recurrent implantation failure.
  

Population-based screening for carriers of genetic diseases and advances in neonatal and pediatric genetic testing have resulted in more and more couples identified as at-risk for inherited disorders. Increasingly, women in these couples ask their ObGyn about their options for future pregnancies.

For some women, genetic testing of a pregnancy as early as possible—even before implantation—is desirable. In vitro fertilization affords such direct access to the genetic material of either gametes before fertilization (i.e., polar-body biopsy) or blastomeres once fertilization has occurred (blastomere biopsy). Complex genetic analysis of these single cells is now possible. Because polar-body biopsy is restricted to testing for maternal disease, blastomere biopsy has gained favor as the method of choice for genetic testing of preimplantation pregnancies.

The duality of genetic testing

Regardless of what genetic material is tested, preimplantation genetic testing encompasses two distinct categories: preimplantation genetic diagnosis, or PGD, and preimplantation genetic screening, or PGS.

What is PGD?

Here, testing is confined to women at risk of an offspring with an identified genetic abnormality. These women, or their partner, typically carry a gene mutation that, alone or in combination with another mutation in the same gene, would result in an identifiable outcome in their child (for example, autosomal-recessive, autosomal-dominant, and X-linked disorders).

PGD, by definition, also includes testing of women, or their partner, who possess a balanced chromosome rearrangement (translocation, inversion). Offspring of carriers of balanced chromosome rearrangements are at increased risk of particular genetic abnormalities, as a result of unbalanced segregation of chromosomes involved in their rearrangement.

How does PGS differ from PGD?

Screening, in contrast, focuses analysis on offspring of women who are theoretically at increased risk of a genetic abnormality based on their age or reproductive history, not on their genetic makeup. PGS looks specifically for chromosomal content, and is based on the premise that decreasing the rate of aneuploidy among the conceptions of women 1) of advanced maternal age, 2) who experience habitual miscarriage, or 3) who have failed multiple cycles of in vitro fertilization (IVF) would increase the rate of implantation and, ultimately, the live birth rate.

The articles below, beginning with a committee opinion from the American Society for Reproductive Medicine (ASRM), address the following:

• evidence in support of PGD for genetic disease
  
• caution about using PGS, in its current format, for aneuploidy screening.
  

PGD can reduce the risk of a child with a specific genetic abnormality carried by one or both parents

Practice Committee of the Society for Assisted Reproductive Technology; Practice Committee of the American Society for Reproductive Medicine. Preimplantation genetic testing: a Practice Committee opinion. Fertil Steril. 2007;88:1497–1504.

A gene mutation carried by one or both parents can increase the risk that their offspring will be affected with an inherited condition. Common examples include autosomal-recessive disorders such as cystic fibrosis; autosomal-dominant disorders such as neurofibromatosis; and X-linked disorders such as hemophilia A.

Recently, human leukocyte antigens (HLA) have been assessed in conjunction with testing for specific genetic diseases, such as Fanconi anemia. In these settings, the intent is to recognize not only the blastomeres that are free of Fanconi anemia, but also those that are potential HLA matches and, therefore, potential donors for an (older) affected sibling.

PGD has been extended to women, or their partner, who possess a gene mutation that places them at increased risk of cancer (such as BRCA-1) and who wish to avoid transmitting that risk-conferring gene to their offspring.

For these diseases, and for many others, knowledge of the specific genetic mutation enables similar molecular testing to be accomplished on a single cell, such as a blastomere.

Technical concerns of testing must be part
of the physician–patient discussion

Typically, PGD analysis is initiated by polymerase chain reaction (PCR) of DNA content extracted from the single cell. This is followed by application of mutation-appropriate molecular technology. Given 1) the short time in which these PGD results are needed (often, 24 to 48 hours) and 2) the limited amount of genetic material available for analysis, technical restraints on testing are recognized:

• Extraneous DNA contamination remains a problem with molecular technology, despite application of intracytoplasmic sperm injection
  
• Only partial amplification of the allele may occur, or allele “drop-out” may be present; both of these phenomena can cause false-negative results
  
• Error can occur dually: 1) Presumably unaffected embryos that are, indeed, affected are transferred and 2) actually normal embryos that have been interpreted incorrectly as abnormal are discarded
  
• The rate of misdiagnosis (false-negative results) ranges from 2% (with autosomal-recessive disorders) to 10% (with autosomal-dominant disorders), although this rate can be lessened with the use of linked markers.
  

PGD for investigating balanced chromosome rearrangements

These rearrangements represent another type of genetic abnormality in which PGD can reduce the likelihood of a conception that carries a specific genetic abnormality.

When one parent carries a balanced chromosome translocation, fluorescence in-situ hybridization (FISH) can be applied to assess the segregation of at-risk chromosomes in a single blastomere cell. In this technique, fluorescence-labeled DNA probes, selected for specificity to the translocation in question, are applied to the single cell fixed on a glass slide. Copies of the DNA segment and, by inference, the chromosomal segment in question are assessed by quantification of the sites of positive fluorescence.

Because translocation carriers are, theoretically, at high risk of transmission of an unbalanced segregant to the blastomere, as many as 10 blastomeres will often be screened until one or two are deemed normal for the FISH probes in question. When implantation does succeed after FISH analysis for a chromosome rearrangement, however, the pregnancy loss rate is lower and the likelihood of a live birth is higher.

Again, in-depth consultation is needed before PGD

Whether PGD is planned for investigating a single-gene disorder or a chromosome translocation, detailed consultation with the woman or the couple is important. This effort should include not only genetic counseling about inheritance, the natural history of the disorder in question, and other options for avoiding the transmission of the disorder—in addition, additional time should be spent describing:

• risks associated with IVF procedures and embryo biopsy (and with extended culture, if needed)
  
• technical limitations of the particular testing that is being considered
  
• options for prenatal testing during a pregnancy
  
• the possibility that embryos suitable for transfer will not be found (and that, potentially, erroneously tested normal embryos will not be transferred)
  
• disposition of embryos in which test results are inconclusive.
  

PGS for women at increased risk of aneuploidy isn’t supported by evidence; consider it investigational

Mastenbroek S, Twisk M, van Echten-Arends J, et al. In vitro fertilization with preimplantation genetic screening. N Engl J Med. 2007;357:9–17.

Mersereau JE, Pergament E, Zhang X, Milad MP. Preimplantation genetic screening to improve in vitro fertilization pregnancy rates: a prospective randomized controlled trial. Fertil Steril. 2008;90:1287–1289.

Aneuploidy contributes to pregnancy loss among women as they become older. Theoretically, avoiding aneuploid pregnancy among embryos transferred during IVF cycles—in older women and in women experiencing multiple pregnancy losses and failed IVF cycles—was expected to increase the implantation rate and decrease the rate of pregnancy loss.

This hypothesis was supported, at first, by observational trials. But at least one randomized study, by Staessen and colleagues,¹ failed to demonstrate that PGS is beneficial in women of advanced maternal age.

Now, a large multicenter, randomized, double-blind, controlled trial conducted by Mastenbroek and co-workers provides further evidence that PGS does not increase the rate of pregnancy and, in fact, significantly reduces that rate among women of advanced maternal age.

The Mastenbroek study compared outcomes among 206 women who had PGS and 202 women who did not. Both groups were matched for maternal age older than 35 years. Blastomeres were analyzed for eight chromosomes, including those known to be highly associated with miscarriage (1, 16, 17, 13, 18, and 21; X and Y).

Among women who underwent PGS, 25% had an ongoing pregnancy of at least 12 weeks’ gestation, compared with 37% of unscreened women. A similar higher rate of live birth was seen among unscreened women (35%, versus 24% in the PGS group).

Mastenbroek’s results are comparable to what was reported from an earlier randomized trial of PGS,¹ in which the implantation rate as the primary outcome among women who had PGS and among controls was not significantly different. Contributors to 1) the lack of success of PGS and 2) the apparent detriment of PGS to the ongoing pregnancy rate include:

• potential for damage to the embryo at biopsy
  
• limitations imposed by FISH technology on the number of probes that can be accurately assessed technically
  
• a growing knowledge that a significant percentage of embryos are chromosomal mosaics at this stage—a phenomenon that likely results in nontransfer of embryos that have the potential for developing karyotypically normally.
  

Does PGS improve outcomes?

More recently, Mersereau and colleagues reported pilot results from a prospective, randomized, controlled trial that assessed whether PGS could improve pregnancy outcomes. Here, selection of infertile women for the study was not restricted to poor prognosis categories, such as advanced maternal age and recurrent pregnancy loss.

Using the live birth rate as the outcome measure, PGS for seven chromosomes was determined not to be associated with a significantly increased live birth rate among screened pregnancies. Sample sizes had been calculated to establish, with significance, a 50% increase in live births—from 30% in the control (unscreened) population to 45% in the screened population. Secondary endpoints, such as the implantation rate and pregnancy loss, also did not differ significantly between the PGS cases and controls.

Again, technical difficulties of two-blastomere biopsy, with its potential for embryo damage, and the presence of underlying embryo mosaicism represent possible barriers to improving the live birth rate when utilizing PGS.

Technical limitations may be one of the largest obstacles
to applying PGS

Practice Committee of the Society for Assisted Reproductive Technology; Practice Committee of the American Society for Reproductive Medicine. Preimplantation genetic testing: a Practice Committee opinion. Fertil Steril. 2007;88:1497–1504.

FISH probes can be chosen to reflect the nature of a given patient’s risk (advanced maternal age, recurrent pregnancy loss) when performing PGS, but the technique itself is limited by the number of probe sites that can be interpreted accurately at one time. Typically, analysis of more than five chromosomes requires two cycles of hybridization, with their associated time requirement and potential for degradation of the single cell.

Alternatively, advances in the analysis of all 23 chromosomes through comparative genomic hybridization may, ultimately, provide an avenue for applying PGS. At the moment, time limitations prohibit comparative genomic hybridization without embryo cryopreservation. Further investigation of other technical limitations, such as the high rate of mosaicism, has revealed that, when two cells are examined and found to be karyotypically discordant, further analysis of the entire embryo will reveal that more than 50% of embryos are, in fact, euploid—that is, chromosomally normal. Random biopsy of the abnormal cell solely would relegate the embryo to nontransfer, despite the predominance of an underlying euploid state.

Understanding of the potential that embryos have to self-correct early mosaicism is growing; we now know that almost one half of embryos identified as aneuploid at cleavage stage correct to euploid if they survive to blastocyst stage. A karyotypic abnormality in a single cell from a day-3 embryo does not always signal an abnormal embryo.

ASRM does not support PGS to improve the live birth rate

This determination by ASRM is based on available evidence about advanced maternal age, recurrent pregnancy loss, recurrent implantation failure, and recurrent aneuploidy loss:

• In women of advanced maternal age, many day-3 embryos display aneuploidy when studied by FISH. In theory, exclusion of these embryos for transfer should improve implantation and live birth rates, but evidence does not support that premise.
  
• Because almost 70% of spontaneous pregnancy loss is caused by a karyotypic abnormality, and women with karyotypically recurrent pregnancy loss are more likely to experience subsequent loss with karyotype abnormalities, the premise of preimplantation screening for aneuploidy also appeared to be well founded. Studies at this time are limited to retrospective series, without randomized controlled trials published.
  
• Among women who experience repeated implantation failure, a finding of more than 50% abnormal embryos isn’t uncommon, yet several studies have not supported an increased implantation rate or live birth rate after PGS.
  

A literature review of PGS calls its introduction “premature”

Gleicher N, Weghofer A, Barad D. Preimplantation genetic screening: “established” and ready for prime time? Fertil Steril. 2008;89:780–788.

After ASRM recognized PGD as an established technique in a 2001 committee opinion, extension of this status to PGS was inadvertently assumed. But PGS is a different testing modality—with different indications, risk/benefit profiles, and efficacy than PGD.

Today, FISH probes are utilized for PGS; the false-negative rate of FISH appears to be driven by the technical constraints of the technology. Potentially increasing the false-negative rate are inadequate hybridization and the use of increasing numbers of probes and hybridization cycles.

Conversely, the false-positive rate—the number of embryos not transferred that are, in fact, chromosomally normal—varies markedly from one study to another, and may be as high as 20% when discarded embryos are more completely assessed.

Similarly, laboratories utilize different methods of obtaining the genetic material. These methods range from biopsy of polar bodies to single-cell blastomere and routine two-cell blastomere biopsy—and, more recently, to blastocyst biopsy. The impact of these various embryo manipulations has yet to be fully considered. Whether biopsy affects the embryo has received little attention.

In fact, embryos that are of poor quality before biopsy—such as those found in women of advanced maternal age—may be more susceptible to the effects of biopsy. The outcome with such embryos may be of even greater detriment to the implantation rate (as discussed in regard to the Mastenbroek study earlier in this article).

The logic of performing PGS for aneuploidy in women of advanced maternal age was reasonable. But this group of women—in whom ovarian reserve is diminished, who respond poorly to ovulation induction, thereby limiting the total number of embryos for analysis and the poorer quality embryos possibly further impaired by the biopsy itself—represent the population that may be least amenable to PGS.

A further observation about PGS in women who have experienced recurrent pregnancy loss or IVF failure: Any impairment of embryos that is a consequence of the method of biopsy may further undermine the generally unsupportive results of PGS that have been documented in these patients.

Consensus on performing PGS

An assessment of European studies and practices reveals similar concerns voiced by the European Society for Human Reproduction and Embryology (ESHRE) PGD Consortium Steering Committee. The committee recently asserted a comparable opinion about “the insufficient data that demonstrate PGS is indeed a cost-effective alternative for standard IVF.”² Gleicher and colleagues, in their review of the literature, conclude that the indications for PGS are currently undefined and, as such, screening should be considered experimental.

Gleicher’s sentiments echo the recommendations of ASRM that, when PGS is considered,

• patients undergo counseling about its limitations, risk of error, and lack of evidence that it improves the live-birth rate
  
• available evidence does not support improvement in the live birth rate in women of advanced maternal age, who have failed previous implantation, who have experienced recurrent pregnancy loss, or who have experienced recurrent pregnancy loss specifically related to aneuploidy
  
• decisions about management should not be based on aneuploidy results of prior PGS cycles for a woman who has experienced recurrent implantation failure.
  

Population-based screening for carriers of genetic diseases and advances in neonatal and pediatric genetic testing have resulted in more and more couples identified as at-risk for inherited disorders. Increasingly, women in these couples ask their ObGyn about their options for future pregnancies.

For some women, genetic testing of a pregnancy as early as possible—even before implantation—is desirable. In vitro fertilization affords such direct access to the genetic material of either gametes before fertilization (i.e., polar-body biopsy) or blastomeres once fertilization has occurred (blastomere biopsy). Complex genetic analysis of these single cells is now possible. Because polar-body biopsy is restricted to testing for maternal disease, blastomere biopsy has gained favor as the method of choice for genetic testing of preimplantation pregnancies.

The duality of genetic testing

Regardless of what genetic material is tested, preimplantation genetic testing encompasses two distinct categories: preimplantation genetic diagnosis, or PGD, and preimplantation genetic screening, or PGS.

What is PGD?

Here, testing is confined to women at risk of an offspring with an identified genetic abnormality. These women, or their partner, typically carry a gene mutation that, alone or in combination with another mutation in the same gene, would result in an identifiable outcome in their child (for example, autosomal-recessive, autosomal-dominant, and X-linked disorders).

PGD, by definition, also includes testing of women, or their partner, who possess a balanced chromosome rearrangement (translocation, inversion). Offspring of carriers of balanced chromosome rearrangements are at increased risk of particular genetic abnormalities, as a result of unbalanced segregation of chromosomes involved in their rearrangement.

How does PGS differ from PGD?

Screening, in contrast, focuses analysis on offspring of women who are theoretically at increased risk of a genetic abnormality based on their age or reproductive history, not on their genetic makeup. PGS looks specifically for chromosomal content, and is based on the premise that decreasing the rate of aneuploidy among the conceptions of women 1) of advanced maternal age, 2) who experience habitual miscarriage, or 3) who have failed multiple cycles of in vitro fertilization (IVF) would increase the rate of implantation and, ultimately, the live birth rate.

The articles below, beginning with a committee opinion from the American Society for Reproductive Medicine (ASRM), address the following:

• evidence in support of PGD for genetic disease
  
• caution about using PGS, in its current format, for aneuploidy screening.
  

PGD can reduce the risk of a child with a specific genetic abnormality carried by one or both parents

Practice Committee of the Society for Assisted Reproductive Technology; Practice Committee of the American Society for Reproductive Medicine. Preimplantation genetic testing: a Practice Committee opinion. Fertil Steril. 2007;88:1497–1504.

A gene mutation carried by one or both parents can increase the risk that their offspring will be affected with an inherited condition. Common examples include autosomal-recessive disorders such as cystic fibrosis; autosomal-dominant disorders such as neurofibromatosis; and X-linked disorders such as hemophilia A.

Recently, human leukocyte antigens (HLA) have been assessed in conjunction with testing for specific genetic diseases, such as Fanconi anemia. In these settings, the intent is to recognize not only the blastomeres that are free of Fanconi anemia, but also those that are potential HLA matches and, therefore, potential donors for an (older) affected sibling.

PGD has been extended to women, or their partner, who possess a gene mutation that places them at increased risk of cancer (such as BRCA-1) and who wish to avoid transmitting that risk-conferring gene to their offspring.

For these diseases, and for many others, knowledge of the specific genetic mutation enables similar molecular testing to be accomplished on a single cell, such as a blastomere.

Technical concerns of testing must be part
of the physician–patient discussion

Typically, PGD analysis is initiated by polymerase chain reaction (PCR) of DNA content extracted from the single cell. This is followed by application of mutation-appropriate molecular technology. Given 1) the short time in which these PGD results are needed (often, 24 to 48 hours) and 2) the limited amount of genetic material available for analysis, technical restraints on testing are recognized:

• Extraneous DNA contamination remains a problem with molecular technology, despite application of intracytoplasmic sperm injection
  
• Only partial amplification of the allele may occur, or allele “drop-out” may be present; both of these phenomena can cause false-negative results
  
• Error can occur dually: 1) Presumably unaffected embryos that are, indeed, affected are transferred and 2) actually normal embryos that have been interpreted incorrectly as abnormal are discarded
  
• The rate of misdiagnosis (false-negative results) ranges from 2% (with autosomal-recessive disorders) to 10% (with autosomal-dominant disorders), although this rate can be lessened with the use of linked markers.
  

PGD for investigating balanced chromosome rearrangements

These rearrangements represent another type of genetic abnormality in which PGD can reduce the likelihood of a conception that carries a specific genetic abnormality.

When one parent carries a balanced chromosome translocation, fluorescence in-situ hybridization (FISH) can be applied to assess the segregation of at-risk chromosomes in a single blastomere cell. In this technique, fluorescence-labeled DNA probes, selected for specificity to the translocation in question, are applied to the single cell fixed on a glass slide. Copies of the DNA segment and, by inference, the chromosomal segment in question are assessed by quantification of the sites of positive fluorescence.

Because translocation carriers are, theoretically, at high risk of transmission of an unbalanced segregant to the blastomere, as many as 10 blastomeres will often be screened until one or two are deemed normal for the FISH probes in question. When implantation does succeed after FISH analysis for a chromosome rearrangement, however, the pregnancy loss rate is lower and the likelihood of a live birth is higher.

Again, in-depth consultation is needed before PGD

Whether PGD is planned for investigating a single-gene disorder or a chromosome translocation, detailed consultation with the woman or the couple is important. This effort should include not only genetic counseling about inheritance, the natural history of the disorder in question, and other options for avoiding the transmission of the disorder—in addition, additional time should be spent describing:

• risks associated with IVF procedures and embryo biopsy (and with extended culture, if needed)
  
• technical limitations of the particular testing that is being considered
  
• options for prenatal testing during a pregnancy
  
• the possibility that embryos suitable for transfer will not be found (and that, potentially, erroneously tested normal embryos will not be transferred)
  
• disposition of embryos in which test results are inconclusive.
  

PGS for women at increased risk of aneuploidy isn’t supported by evidence; consider it investigational

Mastenbroek S, Twisk M, van Echten-Arends J, et al. In vitro fertilization with preimplantation genetic screening. N Engl J Med. 2007;357:9–17.

Mersereau JE, Pergament E, Zhang X, Milad MP. Preimplantation genetic screening to improve in vitro fertilization pregnancy rates: a prospective randomized controlled trial. Fertil Steril. 2008;90:1287–1289.

Aneuploidy contributes to pregnancy loss among women as they become older. Theoretically, avoiding aneuploid pregnancy among embryos transferred during IVF cycles—in older women and in women experiencing multiple pregnancy losses and failed IVF cycles—was expected to increase the implantation rate and decrease the rate of pregnancy loss.

This hypothesis was supported, at first, by observational trials. But at least one randomized study, by Staessen and colleagues,¹ failed to demonstrate that PGS is beneficial in women of advanced maternal age.

Now, a large multicenter, randomized, double-blind, controlled trial conducted by Mastenbroek and co-workers provides further evidence that PGS does not increase the rate of pregnancy and, in fact, significantly reduces that rate among women of advanced maternal age.

The Mastenbroek study compared outcomes among 206 women who had PGS and 202 women who did not. Both groups were matched for maternal age older than 35 years. Blastomeres were analyzed for eight chromosomes, including those known to be highly associated with miscarriage (1, 16, 17, 13, 18, and 21; X and Y).

Among women who underwent PGS, 25% had an ongoing pregnancy of at least 12 weeks’ gestation, compared with 37% of unscreened women. A similar higher rate of live birth was seen among unscreened women (35%, versus 24% in the PGS group).

Mastenbroek’s results are comparable to what was reported from an earlier randomized trial of PGS,¹ in which the implantation rate as the primary outcome among women who had PGS and among controls was not significantly different. Contributors to 1) the lack of success of PGS and 2) the apparent detriment of PGS to the ongoing pregnancy rate include:

• potential for damage to the embryo at biopsy
  
• limitations imposed by FISH technology on the number of probes that can be accurately assessed technically
  
• a growing knowledge that a significant percentage of embryos are chromosomal mosaics at this stage—a phenomenon that likely results in nontransfer of embryos that have the potential for developing karyotypically normally.
  

Does PGS improve outcomes?

More recently, Mersereau and colleagues reported pilot results from a prospective, randomized, controlled trial that assessed whether PGS could improve pregnancy outcomes. Here, selection of infertile women for the study was not restricted to poor prognosis categories, such as advanced maternal age and recurrent pregnancy loss.

Using the live birth rate as the outcome measure, PGS for seven chromosomes was determined not to be associated with a significantly increased live birth rate among screened pregnancies. Sample sizes had been calculated to establish, with significance, a 50% increase in live births—from 30% in the control (unscreened) population to 45% in the screened population. Secondary endpoints, such as the implantation rate and pregnancy loss, also did not differ significantly between the PGS cases and controls.

Again, technical difficulties of two-blastomere biopsy, with its potential for embryo damage, and the presence of underlying embryo mosaicism represent possible barriers to improving the live birth rate when utilizing PGS.

Technical limitations may be one of the largest obstacles
to applying PGS

Practice Committee of the Society for Assisted Reproductive Technology; Practice Committee of the American Society for Reproductive Medicine. Preimplantation genetic testing: a Practice Committee opinion. Fertil Steril. 2007;88:1497–1504.

FISH probes can be chosen to reflect the nature of a given patient’s risk (advanced maternal age, recurrent pregnancy loss) when performing PGS, but the technique itself is limited by the number of probe sites that can be interpreted accurately at one time. Typically, analysis of more than five chromosomes requires two cycles of hybridization, with their associated time requirement and potential for degradation of the single cell.

Alternatively, advances in the analysis of all 23 chromosomes through comparative genomic hybridization may, ultimately, provide an avenue for applying PGS. At the moment, time limitations prohibit comparative genomic hybridization without embryo cryopreservation. Further investigation of other technical limitations, such as the high rate of mosaicism, has revealed that, when two cells are examined and found to be karyotypically discordant, further analysis of the entire embryo will reveal that more than 50% of embryos are, in fact, euploid—that is, chromosomally normal. Random biopsy of the abnormal cell solely would relegate the embryo to nontransfer, despite the predominance of an underlying euploid state.

Understanding of the potential that embryos have to self-correct early mosaicism is growing; we now know that almost one half of embryos identified as aneuploid at cleavage stage correct to euploid if they survive to blastocyst stage. A karyotypic abnormality in a single cell from a day-3 embryo does not always signal an abnormal embryo.

ASRM does not support PGS to improve the live birth rate

This determination by ASRM is based on available evidence about advanced maternal age, recurrent pregnancy loss, recurrent implantation failure, and recurrent aneuploidy loss:

• In women of advanced maternal age, many day-3 embryos display aneuploidy when studied by FISH. In theory, exclusion of these embryos for transfer should improve implantation and live birth rates, but evidence does not support that premise.
  
• Because almost 70% of spontaneous pregnancy loss is caused by a karyotypic abnormality, and women with karyotypically recurrent pregnancy loss are more likely to experience subsequent loss with karyotype abnormalities, the premise of preimplantation screening for aneuploidy also appeared to be well founded. Studies at this time are limited to retrospective series, without randomized controlled trials published.
  
• Among women who experience repeated implantation failure, a finding of more than 50% abnormal embryos isn’t uncommon, yet several studies have not supported an increased implantation rate or live birth rate after PGS.
  

A literature review of PGS calls its introduction “premature”

Gleicher N, Weghofer A, Barad D. Preimplantation genetic screening: “established” and ready for prime time? Fertil Steril. 2008;89:780–788.

After ASRM recognized PGD as an established technique in a 2001 committee opinion, extension of this status to PGS was inadvertently assumed. But PGS is a different testing modality—with different indications, risk/benefit profiles, and efficacy than PGD.

Today, FISH probes are utilized for PGS; the false-negative rate of FISH appears to be driven by the technical constraints of the technology. Potentially increasing the false-negative rate are inadequate hybridization and the use of increasing numbers of probes and hybridization cycles.

Conversely, the false-positive rate—the number of embryos not transferred that are, in fact, chromosomally normal—varies markedly from one study to another, and may be as high as 20% when discarded embryos are more completely assessed.

Similarly, laboratories utilize different methods of obtaining the genetic material. These methods range from biopsy of polar bodies to single-cell blastomere and routine two-cell blastomere biopsy—and, more recently, to blastocyst biopsy. The impact of these various embryo manipulations has yet to be fully considered. Whether biopsy affects the embryo has received little attention.

In fact, embryos that are of poor quality before biopsy—such as those found in women of advanced maternal age—may be more susceptible to the effects of biopsy. The outcome with such embryos may be of even greater detriment to the implantation rate (as discussed in regard to the Mastenbroek study earlier in this article).

The logic of performing PGS for aneuploidy in women of advanced maternal age was reasonable. But this group of women—in whom ovarian reserve is diminished, who respond poorly to ovulation induction, thereby limiting the total number of embryos for analysis and the poorer quality embryos possibly further impaired by the biopsy itself—represent the population that may be least amenable to PGS.

A further observation about PGS in women who have experienced recurrent pregnancy loss or IVF failure: Any impairment of embryos that is a consequence of the method of biopsy may further undermine the generally unsupportive results of PGS that have been documented in these patients.

Consensus on performing PGS

An assessment of European studies and practices reveals similar concerns voiced by the European Society for Human Reproduction and Embryology (ESHRE) PGD Consortium Steering Committee. The committee recently asserted a comparable opinion about “the insufficient data that demonstrate PGS is indeed a cost-effective alternative for standard IVF.”² Gleicher and colleagues, in their review of the literature, conclude that the indications for PGS are currently undefined and, as such, screening should be considered experimental.

Gleicher’s sentiments echo the recommendations of ASRM that, when PGS is considered,

• patients undergo counseling about its limitations, risk of error, and lack of evidence that it improves the live-birth rate
  
• available evidence does not support improvement in the live birth rate in women of advanced maternal age, who have failed previous implantation, who have experienced recurrent pregnancy loss, or who have experienced recurrent pregnancy loss specifically related to aneuploidy
  
• decisions about management should not be based on aneuploidy results of prior PGS cycles for a woman who has experienced recurrent implantation failure.
  

Dr. Dayspring serves on the advisory board for LipoScience. Dr. Helmbold reports no financial relationships relevant to this article.

Add another item to your ever-growing list of responsibilities: monitoring your patients’ risk of atherosclerosis.

This task used to be the purview of internists and cardiologists but, because gynecologists are increasingly serving as a primary care provider, you need to learn to recognize and diagnose the many clinical expressions of atherosclerosis in your aging patients.

A crucial part of that knowledge is a thorough understanding of each and every lipid concentration parameter reported within the standard lipid profile. This article reviews those parameters, explains how to interpret them individually and in combination, and introduces a new paradigm: the analysis of lipoprotein particle concentrations as a more precise way to determine risk.

If used in its entirety, the lipid profile provides a significant amount of information about the presence or absence of pathologic lipoprotein concentrations. Far too many clinicians focus solely on low-density lipoprotein cholesterol (LDL-C) and ignore the rest of the profile. Failure to consider the other variables is one reason why atherosclerotic disease is underdiagnosed and undertreated in the United States in many patients—especially women.¹

Why lipoproteins are important

There is only one absolute in atherosclerosis: Sterols—predominantly cholesterol—enter the artery wall, where they are oxidized, internalized by macrophages, and transformed into foam cells, the histologic hallmark of atherosclerosis. With the accumulation of foam cells, fatty streaks develop and, ultimately, so does complex plaque.

Lipids associated with cardiovascular disease (CVD) include:

• cholesterol
• noncholesterol sterols such as sitosterol, campesterol, and others of mostly plant or shellfish origin
• triacylglycerol, or triglycerides (TG)
• phospholipids.

Because lipids are insoluble in aqueous solutions such as plasma, they must be “trafficked” within protein-enwrapped particles called lipoproteins. The surface proteins that provide structure and solubility to lipoproteins are called apolipoproteins. A key concept is that, with their surface apolipoproteins and cholesterol core, certain lipoproteins are potential agents of atherogenesis in that they transport sterols into the artery wall.²

Estimation of the risk of CVD involves careful analysis of all standard lipid concentrations and their various ratios, and prediction of the potential presence of atherogenic lipoproteins. Successful prevention or treatment of atherosclerosis entails limiting the presence of atherogenic lipoproteins.

A new paradigm is on its way

The atherogenicity of lipoprotein particles is determined by particle concentration as well as other variables, including particle size, lipid composition, and distinct surface apolipoproteins.

Lipoproteins smaller than 70 nm in diameter are driven into the arterial intima primarily by concentration gradients, regardless of lipid composition or particle size.³ A recent Consensus Statement from the American Diabetes Association and the American College of Cardiology observed that quantitative analysis of these potentially atherogenic lipoproteins is one of the best lipid/lipoprotein-related determinants of CVD risk.⁴ Lipoprotein particle concentrations have emerged not only as superb predictors of risk, but also as goals of therapy.^5-7

Because of cost, third-party reimbursement, varying test availability, and lack of interpretive knowledge, few clinicians routinely order lipoprotein quantification. Historically, CVD risk and goals of therapy have been based on lipid concentrations (the amount of lipids trafficked within lipoprotein cores) reported in the lipid profile. Guidelines from the National Cholesterol Education Program, Adult Treatment Panel III (NCEP ATP-III)^8,9 and the American Heart Association (AHA) CVD Prevention in Women^10,11 use lipid concentrations such as total cholesterol (TC), LDL-C, high-density lipoprotein cholesterol (HDL-C), and TG as estimates or surrogates of lipoprotein concentrations ( TABLE 1 ).

The day is rapidly approaching, however, when lipoprotein concentrations may replace the lipid profile in clinical practice. It is critical that clinicians develop a solid understanding of lipoprotein physiology and pathology.^7,12 It also is crucial that we be as skilled as possible in accurately predicting lipoprotein pathology using all of the lipid concentration parameters present in the lipid panel.

TABLE 1

Desirable lipid values for women

How lipoproteins are analyzed

Lipoproteins can be separated into their components using any of several methodologies, including ultracentrifugation, electrophoresis, apolipoprotein content analysis, and nuclear magnetic resonance (NMR) spectroscopy. Of these, only the last two provide information on particle concentrations.^13,14

Apolipoprotein content analysis reveals two major categories of particles:

• alpha-lipoproteins, or HDL, which contain two to four molecules of apolipoprotein A-I (apoA-I)
• beta-lipoproteins, a collective group of chylomicrons, very-low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), and LDL, each containing a single molecule of apolipoprotein B (apoB). Because of very different half-lives (chylomicrons, 1 hour; VLDL, 2–6 hours; IDL, 1–2 hours; LDL, 2–3 days), the great majority (90% to 95%) of apoB-containing particles are LDL. Although apoB measurement yields quantification of all beta-lipoproteins, it is primarily a surrogate of LDL particle (LDL-P) concentration.¹⁵

Individual particle concentrations, determined by NMR spectroscopy, are reported as VLDL-P, IDL-P, LDL-P, and HDL-P (see the “Glossary”).¹⁴

Several epidemiologic studies that enrolled both genders found the best predictors of risk to be:

• elevated levels of apoB or LDL-P and reduced levels of apoA-I or HDL-P
• a high apoB/apoA-I ratio or LDL-P/HDL-P ratio.^6,13,14

After adjustment for lipoprotein concentration data (apoB or LDL-P), other lipoprotein characteristics such as particle lipid content, size, or composition, for the most part, had no statistically significant relationship with the risk of cardiovascular disease.^16,17

Lipids and lipoproteins: A glossary

Using lipid measurements to estimate lipoproteins

Total cholesterol represents the cholesterol content within all lipoproteins in 1 dL of plasma. Because beta-lipoproteins are considerably larger than alpha-lipoproteins, approximately 75% of total cholesterol is carried in the apoB-containing particles, making TC an apoB surrogate.

VLDL-C, an often ignored variable, is not measured but calculated using the Friedewald formula, dividing TG by five. This calculation assumes—often erroneously as TG levels rise—that TG consists only of VLDL particles and that VLDL composition contains five times more TG than cholesterol molecules.

A desirable TG level is <150 mg/dL, so normal VLDL-C is 150/5 or <30 mg/dL.

LDL-C is also an apoB surrogate

Although VLDL-C is a weak apoB surrogate,¹⁵ data from the Framingham Heart Study showed it to be a good predictor of VLDL remnant particles.¹⁸ However, because the vast majority of beta-lipoproteins are LDL, LDL-C (especially if elevated) is a better apoB surrogate than VLDL-C and is the primary CVD risk factor and goal of therapy in every current guideline.

LDL-C is usually a calculated value using the formula:

LDL-C = TC – (HDL-C + VLDL-C)

Upon special order, laboratories can directly measure LDL-C. This option is most useful when TG levels are high, rendering the Friedewald formula less accurate ( TABLE 2 ).¹⁹ For population cut points and desirable goals of therapy for lipid and lipoprotein concentrations, see the FIGURE .

TABLE 2

How lipid concentrations are determined

FIGURE Population percentile cut points and goals for LDL-C, LDL-P, ApoB, and non-HDL-C

HDL-C, apoA-I are inversely related to cardiovascular risk

The epidemiologic data strongly indicate that both HDL-C and apoA-I are strongly and inversely related to CVD risk.⁶ HDL particles are a heterogenous collection of:

• unlipidated apoA-I
• very small pre-beta HDL
• more mature, lipidated HDL3 and HDL2 species (HDL3 smaller than HDL2).

NMR nomenclature identifies the smaller HDL species as H1 and H2 and the larger HDL species as H4 and H5.¹⁴ The smaller HDL species also contain apoA-II.

Although HDL can acquire cholesterol from any cell, including arterial-wall foam cells, the majority of HDL lipidation occurs in the liver or proximal small intestine, after which it is trafficked to steroidogenic tissue, adipocytes, or back to the liver. Normally, HDL carries little TG.²⁰ The only lipid concentration that can serve as a surrogate of apoA-I or HDL-P is HDL-C, where the assumption is that higher HDL-C indicates higher apoA-I, and vice versa.

In reality, the correlation between apoA-I and HDL-C varies because each HDL particle can have from two to four apoA-I molecules, and the volume of cholesterol within the particle is a function of particle size and its TG content. For the most part, total HDL-C is indicative of the cholesterol carried in the larger, mature HDL2 (H4, H5) particles; patients with low HDL-C typically lack these mature, lipidated HDL particles.

Because HDL rapidly and repeatedly lipidates and then delipidates, there is no relationship between the HDL-C level and the complex dynamic process termed reverse cholesterol transport process. Neither HDL-C, nor apoA-I, nor HDL-P, nor HDL size is consistently related to HDL particle functionality—i.e., the ability of HDL to lipidate or delipidate, appropriately traffic cholesterol, or perform numerous other nonlipid antiatherogenic functions.^20,21

Focus on lipoprotein particle concentrations

To most accurately predict lipid-related CVD risk, you must determine which patients have elevated numbers of atherogenic lipoproteins using actual particle concentrations. In most practices, lipoprotein particle numbers must be estimated by scrutinizing all of the lipid concentrations and ratios (not simply LDL-C).

TC and, especially, LDL-C are apoB and LDL-P surrogates, but the best lipid concentration estimate of apoB is the calculated non-HDL-C value. By subtracting HDL-C from TC, it is possible to identify the cholesterol not in the HDL particles but in all of the potentially atherogenic apoB particles. In essence, non-HDL-C is VLDL-C plus LDL-C. This equation yields a better apoB or LDL-P proxy, compared with LDL-C alone.¹⁸ If a patient has reached her LDL-C goal but still has a high non-HDL-C level, we can assume that there are still too many apoB particles and that they are contributing to residual risk.

Because LDL is the predominant apoB species, non-HDL-C is the best lipid concentration predictor of LDL-P.¹⁵ Because neither TC nor HDL-C assays require a patient to fast, non-HDL-C is accurate in nonfasting patients, making it a very practical way to screen for CVD risk.⁸ In the Women’s Health Study, which involved mostly healthy women, non-HDL-C predicted the risk of coronary heart disease as well as apoB did, but not as well as LDL-P.^22,23 In independent, separately published analyses from the Framingham Off-spring Study, LDL-P was a better predictor of risk than LDL-C and apoB.^15,24

NCEP ATP-III guidelines introduced non-HDL-C as a secondary goal of therapy in patients with TG >200 mg/dL. Subsequent data indicate that non-HDL-C is always a better predictor of risk than LDL-C is, regardless of TG levels.¹⁸

The AHA Women’s Guideline was the first to set a desired non-HDL-C level (130 mg/dL) independent of the TG value.¹⁰ Because a normal VLDL-C concentration is 30 mg/dL, the non-HDL-C goal is 30 mg/dL above the desired LDL-C goal. For example, if the desired LDL-C value is 100 mg/dL, the non-HDL-C goal is 130 mg/dL. If the desired LDL-C goal is 70 mg/dL—as it is in a patient at very high risk—the non-HDL-C goal would be 100 mg/dL ( FIGURE ).^9,11

Insulin resistance diminishes accuracy of lipid profile

The ability to predict lipoprotein particle concentrations using the lipid profile becomes far less accurate in situations associated with insulin resistance and metabolic syndrome in patients who have TG-HDL axis disorders. In women, these disorders are typified by an elevation of TG >150 mg/dL and a decrease in HDL-C <50 mg/dL, with borderline or normal LDL-C levels.²⁵

As TG begins to rise above 120 mg/dL, hepatic secretion of TG-rich VLDL particles increases. As VLDL-TG is hydrolyzed by lipoprotein lipase in muscle and fat cells, in a process termed lipolysis, VLDL shrinks and transforms into IDL. Ultimately, unless it is cleared by hepatic LDL receptors, the IDL undergoes additional lipolysis by hepatic lipase and transforms into LDL particles. Because of their longer half-life, these LDL particles accumulate, further elevating apoB and LDL-P.

In the presence of TG-rich VLDL and chylomicrons, additional pathologic particle remodeling occurs. By way of a lipid transfer protein called cholesteryl ester transfer protein (CETP), some of the TG molecules present in TG-rich lipoproteins are exchanged for cholesteryl esters in LDL and HDL. This lipid transfer creates LDL and HDL that are TG-rich and cholesterol-poor, enabling additional TG lipolysis by hepatic lipase to create smaller LDL and HDL. The latter is so small that it can pass through renal glomeruli and be excreted, leading to reductions of HDL-P, apoA-I, and HDL-C.

Also created in this process are smaller, atherogenic, cholesterol-rich VLDL and chylomicron remnants, diagnosable by an elevated VLDL-C. Patients who have this pathology typically have elevated TG, reduced HDL-C, variable LDL-C, and an increased TG/HDL-C ratio (>3.8), which are indicative of too many small LDL particles (high apoB, LDL-P) and reduced number of HDL particles (high apoB/A-I ratio).^26,27

Such a scenario, typical of TG-HDL axis disorders, explains much of the risk associated with rising TG levels and is very common in premenopausal women who have insulin-resistant states such as type 2 diabetes or polycystic ovary syndrome and in menopausal women who have insulin resistance and coronary artery disease.¹

LDL-C and LDL-P do not always correlate

Because the volume of a lipoprotein is a function of its radius cubed (V = 4/3πr³),¹⁴ a patient who has small LDL will require up to 40% to 70% more LDL particles to traffic a given amount of LDL-C. In such a patient, there is often little correlation between LDL-C and LDL-P or apoB values. Regardless of the LDL-C, the apoB, LDL-P, or non-HDL-C is often elevated.²⁸ This risk, which cannot be predicted by looking only at LDL-C, is the main reason guidelines advocate the use of non-HDL-C or the TC/HDL-C ratio.^8,11 (See the case studies.)

In summary, a large part of the risk of CVD seen in patients who have low HDL-C derives from the associated increase in the number of apoB particles, mostly composed of small LDL, as well as an increase in remnant particles.^15,21,28 This crucial point explains why treatment of low HDL-C states should always first target apoB or LDL-P (LDL-C and non-HDL-C), rather than apoA-I or HDL-C ( TABLES 3 and 4 ).^8,9

TABLE 3

Lipid markers of small low-density lipoproteins

TABLE 4

Lipid markers of remnant lipoproteins

A few words of advice

The driving forces of atherogenesis are increased numbers of apoB-containing lipoproteins and impaired endothelial integrity. ApoB and LDL-P are the available lab assays that most accurately quantify atherogenic particle number.

The lipid-concentration surrogates that you should be using to better predict apoB and CVD risk are:

• TC (unless HDL-C is very high)
• LDL-C
• Non-HDL-C
• TC/HDL-C ratio
• TG/HDL-C ratio.

Because LDL is by far the most numerous of the apoB particles present in plasma, it is the primary agent of atherogenesis. However, apoB and LDL-P do not correlate with LDL-C when LDL particles are small, are TG-rich and cholesterol-poor, or simply cholesterol-poor (seen in some patients who have low LDL-C levels).^7,15

Both NCEP ATP-III and AHA Women’s Guidelines use the TC/HDL ratio as a powerful risk predictor. However, as a goal of therapy, these guidelines recommend normalizing LDL-C and then non-HDL-C.^8,11 In reality, normalization of non-HDL-C takes care of LDL-C as well. For example, say a patient has LDL-C <100 mg/dL, but non-HDL-C >130 mg/dL or TC/HDL-C ratio >4. These readings indicate residual risk and suggest that an elevated number of apoB particles is present. Therapy to normalize non-HDL-C or, better yet, apoB/LDL-P, is warranted. The clue that residual risk is present even when LDL-C is normal is the reduction of HDL-C and elevation of TG and non-HDL-C.

Dr. Dayspring serves on the advisory board for LipoScience. Dr. Helmbold reports no financial relationships relevant to this article.

Add another item to your ever-growing list of responsibilities: monitoring your patients’ risk of atherosclerosis.

This task used to be the purview of internists and cardiologists but, because gynecologists are increasingly serving as a primary care provider, you need to learn to recognize and diagnose the many clinical expressions of atherosclerosis in your aging patients.

A crucial part of that knowledge is a thorough understanding of each and every lipid concentration parameter reported within the standard lipid profile. This article reviews those parameters, explains how to interpret them individually and in combination, and introduces a new paradigm: the analysis of lipoprotein particle concentrations as a more precise way to determine risk.

If used in its entirety, the lipid profile provides a significant amount of information about the presence or absence of pathologic lipoprotein concentrations. Far too many clinicians focus solely on low-density lipoprotein cholesterol (LDL-C) and ignore the rest of the profile. Failure to consider the other variables is one reason why atherosclerotic disease is underdiagnosed and undertreated in the United States in many patients—especially women.¹

Why lipoproteins are important

There is only one absolute in atherosclerosis: Sterols—predominantly cholesterol—enter the artery wall, where they are oxidized, internalized by macrophages, and transformed into foam cells, the histologic hallmark of atherosclerosis. With the accumulation of foam cells, fatty streaks develop and, ultimately, so does complex plaque.

Lipids associated with cardiovascular disease (CVD) include:

• cholesterol
• noncholesterol sterols such as sitosterol, campesterol, and others of mostly plant or shellfish origin
• triacylglycerol, or triglycerides (TG)
• phospholipids.

Because lipids are insoluble in aqueous solutions such as plasma, they must be “trafficked” within protein-enwrapped particles called lipoproteins. The surface proteins that provide structure and solubility to lipoproteins are called apolipoproteins. A key concept is that, with their surface apolipoproteins and cholesterol core, certain lipoproteins are potential agents of atherogenesis in that they transport sterols into the artery wall.²

Estimation of the risk of CVD involves careful analysis of all standard lipid concentrations and their various ratios, and prediction of the potential presence of atherogenic lipoproteins. Successful prevention or treatment of atherosclerosis entails limiting the presence of atherogenic lipoproteins.

A new paradigm is on its way

The atherogenicity of lipoprotein particles is determined by particle concentration as well as other variables, including particle size, lipid composition, and distinct surface apolipoproteins.

Lipoproteins smaller than 70 nm in diameter are driven into the arterial intima primarily by concentration gradients, regardless of lipid composition or particle size.³ A recent Consensus Statement from the American Diabetes Association and the American College of Cardiology observed that quantitative analysis of these potentially atherogenic lipoproteins is one of the best lipid/lipoprotein-related determinants of CVD risk.⁴ Lipoprotein particle concentrations have emerged not only as superb predictors of risk, but also as goals of therapy.^5-7

Because of cost, third-party reimbursement, varying test availability, and lack of interpretive knowledge, few clinicians routinely order lipoprotein quantification. Historically, CVD risk and goals of therapy have been based on lipid concentrations (the amount of lipids trafficked within lipoprotein cores) reported in the lipid profile. Guidelines from the National Cholesterol Education Program, Adult Treatment Panel III (NCEP ATP-III)^8,9 and the American Heart Association (AHA) CVD Prevention in Women^10,11 use lipid concentrations such as total cholesterol (TC), LDL-C, high-density lipoprotein cholesterol (HDL-C), and TG as estimates or surrogates of lipoprotein concentrations ( TABLE 1 ).

The day is rapidly approaching, however, when lipoprotein concentrations may replace the lipid profile in clinical practice. It is critical that clinicians develop a solid understanding of lipoprotein physiology and pathology.^7,12 It also is crucial that we be as skilled as possible in accurately predicting lipoprotein pathology using all of the lipid concentration parameters present in the lipid panel.

TABLE 1

Desirable lipid values for women

How lipoproteins are analyzed

Lipoproteins can be separated into their components using any of several methodologies, including ultracentrifugation, electrophoresis, apolipoprotein content analysis, and nuclear magnetic resonance (NMR) spectroscopy. Of these, only the last two provide information on particle concentrations.^13,14

Apolipoprotein content analysis reveals two major categories of particles:

• alpha-lipoproteins, or HDL, which contain two to four molecules of apolipoprotein A-I (apoA-I)
• beta-lipoproteins, a collective group of chylomicrons, very-low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), and LDL, each containing a single molecule of apolipoprotein B (apoB). Because of very different half-lives (chylomicrons, 1 hour; VLDL, 2–6 hours; IDL, 1–2 hours; LDL, 2–3 days), the great majority (90% to 95%) of apoB-containing particles are LDL. Although apoB measurement yields quantification of all beta-lipoproteins, it is primarily a surrogate of LDL particle (LDL-P) concentration.¹⁵

Individual particle concentrations, determined by NMR spectroscopy, are reported as VLDL-P, IDL-P, LDL-P, and HDL-P (see the “Glossary”).¹⁴

Several epidemiologic studies that enrolled both genders found the best predictors of risk to be:

• elevated levels of apoB or LDL-P and reduced levels of apoA-I or HDL-P
• a high apoB/apoA-I ratio or LDL-P/HDL-P ratio.^6,13,14

After adjustment for lipoprotein concentration data (apoB or LDL-P), other lipoprotein characteristics such as particle lipid content, size, or composition, for the most part, had no statistically significant relationship with the risk of cardiovascular disease.^16,17

Lipids and lipoproteins: A glossary

Using lipid measurements to estimate lipoproteins

Total cholesterol represents the cholesterol content within all lipoproteins in 1 dL of plasma. Because beta-lipoproteins are considerably larger than alpha-lipoproteins, approximately 75% of total cholesterol is carried in the apoB-containing particles, making TC an apoB surrogate.

VLDL-C, an often ignored variable, is not measured but calculated using the Friedewald formula, dividing TG by five. This calculation assumes—often erroneously as TG levels rise—that TG consists only of VLDL particles and that VLDL composition contains five times more TG than cholesterol molecules.

A desirable TG level is <150 mg/dL, so normal VLDL-C is 150/5 or <30 mg/dL.

LDL-C is also an apoB surrogate

Although VLDL-C is a weak apoB surrogate,¹⁵ data from the Framingham Heart Study showed it to be a good predictor of VLDL remnant particles.¹⁸ However, because the vast majority of beta-lipoproteins are LDL, LDL-C (especially if elevated) is a better apoB surrogate than VLDL-C and is the primary CVD risk factor and goal of therapy in every current guideline.

LDL-C is usually a calculated value using the formula:

LDL-C = TC – (HDL-C + VLDL-C)

Upon special order, laboratories can directly measure LDL-C. This option is most useful when TG levels are high, rendering the Friedewald formula less accurate ( TABLE 2 ).¹⁹ For population cut points and desirable goals of therapy for lipid and lipoprotein concentrations, see the FIGURE .

TABLE 2

How lipid concentrations are determined

FIGURE Population percentile cut points and goals for LDL-C, LDL-P, ApoB, and non-HDL-C

HDL-C, apoA-I are inversely related to cardiovascular risk

The epidemiologic data strongly indicate that both HDL-C and apoA-I are strongly and inversely related to CVD risk.⁶ HDL particles are a heterogenous collection of:

• unlipidated apoA-I
• very small pre-beta HDL
• more mature, lipidated HDL3 and HDL2 species (HDL3 smaller than HDL2).

NMR nomenclature identifies the smaller HDL species as H1 and H2 and the larger HDL species as H4 and H5.¹⁴ The smaller HDL species also contain apoA-II.

Although HDL can acquire cholesterol from any cell, including arterial-wall foam cells, the majority of HDL lipidation occurs in the liver or proximal small intestine, after which it is trafficked to steroidogenic tissue, adipocytes, or back to the liver. Normally, HDL carries little TG.²⁰ The only lipid concentration that can serve as a surrogate of apoA-I or HDL-P is HDL-C, where the assumption is that higher HDL-C indicates higher apoA-I, and vice versa.

In reality, the correlation between apoA-I and HDL-C varies because each HDL particle can have from two to four apoA-I molecules, and the volume of cholesterol within the particle is a function of particle size and its TG content. For the most part, total HDL-C is indicative of the cholesterol carried in the larger, mature HDL2 (H4, H5) particles; patients with low HDL-C typically lack these mature, lipidated HDL particles.

Because HDL rapidly and repeatedly lipidates and then delipidates, there is no relationship between the HDL-C level and the complex dynamic process termed reverse cholesterol transport process. Neither HDL-C, nor apoA-I, nor HDL-P, nor HDL size is consistently related to HDL particle functionality—i.e., the ability of HDL to lipidate or delipidate, appropriately traffic cholesterol, or perform numerous other nonlipid antiatherogenic functions.^20,21

Focus on lipoprotein particle concentrations

To most accurately predict lipid-related CVD risk, you must determine which patients have elevated numbers of atherogenic lipoproteins using actual particle concentrations. In most practices, lipoprotein particle numbers must be estimated by scrutinizing all of the lipid concentrations and ratios (not simply LDL-C).

TC and, especially, LDL-C are apoB and LDL-P surrogates, but the best lipid concentration estimate of apoB is the calculated non-HDL-C value. By subtracting HDL-C from TC, it is possible to identify the cholesterol not in the HDL particles but in all of the potentially atherogenic apoB particles. In essence, non-HDL-C is VLDL-C plus LDL-C. This equation yields a better apoB or LDL-P proxy, compared with LDL-C alone.¹⁸ If a patient has reached her LDL-C goal but still has a high non-HDL-C level, we can assume that there are still too many apoB particles and that they are contributing to residual risk.

Because LDL is the predominant apoB species, non-HDL-C is the best lipid concentration predictor of LDL-P.¹⁵ Because neither TC nor HDL-C assays require a patient to fast, non-HDL-C is accurate in nonfasting patients, making it a very practical way to screen for CVD risk.⁸ In the Women’s Health Study, which involved mostly healthy women, non-HDL-C predicted the risk of coronary heart disease as well as apoB did, but not as well as LDL-P.^22,23 In independent, separately published analyses from the Framingham Off-spring Study, LDL-P was a better predictor of risk than LDL-C and apoB.^15,24

NCEP ATP-III guidelines introduced non-HDL-C as a secondary goal of therapy in patients with TG >200 mg/dL. Subsequent data indicate that non-HDL-C is always a better predictor of risk than LDL-C is, regardless of TG levels.¹⁸

The AHA Women’s Guideline was the first to set a desired non-HDL-C level (130 mg/dL) independent of the TG value.¹⁰ Because a normal VLDL-C concentration is 30 mg/dL, the non-HDL-C goal is 30 mg/dL above the desired LDL-C goal. For example, if the desired LDL-C value is 100 mg/dL, the non-HDL-C goal is 130 mg/dL. If the desired LDL-C goal is 70 mg/dL—as it is in a patient at very high risk—the non-HDL-C goal would be 100 mg/dL ( FIGURE ).^9,11

Insulin resistance diminishes accuracy of lipid profile

The ability to predict lipoprotein particle concentrations using the lipid profile becomes far less accurate in situations associated with insulin resistance and metabolic syndrome in patients who have TG-HDL axis disorders. In women, these disorders are typified by an elevation of TG >150 mg/dL and a decrease in HDL-C <50 mg/dL, with borderline or normal LDL-C levels.²⁵

As TG begins to rise above 120 mg/dL, hepatic secretion of TG-rich VLDL particles increases. As VLDL-TG is hydrolyzed by lipoprotein lipase in muscle and fat cells, in a process termed lipolysis, VLDL shrinks and transforms into IDL. Ultimately, unless it is cleared by hepatic LDL receptors, the IDL undergoes additional lipolysis by hepatic lipase and transforms into LDL particles. Because of their longer half-life, these LDL particles accumulate, further elevating apoB and LDL-P.

In the presence of TG-rich VLDL and chylomicrons, additional pathologic particle remodeling occurs. By way of a lipid transfer protein called cholesteryl ester transfer protein (CETP), some of the TG molecules present in TG-rich lipoproteins are exchanged for cholesteryl esters in LDL and HDL. This lipid transfer creates LDL and HDL that are TG-rich and cholesterol-poor, enabling additional TG lipolysis by hepatic lipase to create smaller LDL and HDL. The latter is so small that it can pass through renal glomeruli and be excreted, leading to reductions of HDL-P, apoA-I, and HDL-C.

Also created in this process are smaller, atherogenic, cholesterol-rich VLDL and chylomicron remnants, diagnosable by an elevated VLDL-C. Patients who have this pathology typically have elevated TG, reduced HDL-C, variable LDL-C, and an increased TG/HDL-C ratio (>3.8), which are indicative of too many small LDL particles (high apoB, LDL-P) and reduced number of HDL particles (high apoB/A-I ratio).^26,27

Such a scenario, typical of TG-HDL axis disorders, explains much of the risk associated with rising TG levels and is very common in premenopausal women who have insulin-resistant states such as type 2 diabetes or polycystic ovary syndrome and in menopausal women who have insulin resistance and coronary artery disease.¹

LDL-C and LDL-P do not always correlate

Because the volume of a lipoprotein is a function of its radius cubed (V = 4/3πr³),¹⁴ a patient who has small LDL will require up to 40% to 70% more LDL particles to traffic a given amount of LDL-C. In such a patient, there is often little correlation between LDL-C and LDL-P or apoB values. Regardless of the LDL-C, the apoB, LDL-P, or non-HDL-C is often elevated.²⁸ This risk, which cannot be predicted by looking only at LDL-C, is the main reason guidelines advocate the use of non-HDL-C or the TC/HDL-C ratio.^8,11 (See the case studies.)

In summary, a large part of the risk of CVD seen in patients who have low HDL-C derives from the associated increase in the number of apoB particles, mostly composed of small LDL, as well as an increase in remnant particles.^15,21,28 This crucial point explains why treatment of low HDL-C states should always first target apoB or LDL-P (LDL-C and non-HDL-C), rather than apoA-I or HDL-C ( TABLES 3 and 4 ).^8,9

TABLE 3

Lipid markers of small low-density lipoproteins

TABLE 4

Lipid markers of remnant lipoproteins

A few words of advice

The driving forces of atherogenesis are increased numbers of apoB-containing lipoproteins and impaired endothelial integrity. ApoB and LDL-P are the available lab assays that most accurately quantify atherogenic particle number.

The lipid-concentration surrogates that you should be using to better predict apoB and CVD risk are:

• TC (unless HDL-C is very high)
• LDL-C
• Non-HDL-C
• TC/HDL-C ratio
• TG/HDL-C ratio.

Because LDL is by far the most numerous of the apoB particles present in plasma, it is the primary agent of atherogenesis. However, apoB and LDL-P do not correlate with LDL-C when LDL particles are small, are TG-rich and cholesterol-poor, or simply cholesterol-poor (seen in some patients who have low LDL-C levels).^7,15

Both NCEP ATP-III and AHA Women’s Guidelines use the TC/HDL ratio as a powerful risk predictor. However, as a goal of therapy, these guidelines recommend normalizing LDL-C and then non-HDL-C.^8,11 In reality, normalization of non-HDL-C takes care of LDL-C as well. For example, say a patient has LDL-C <100 mg/dL, but non-HDL-C >130 mg/dL or TC/HDL-C ratio >4. These readings indicate residual risk and suggest that an elevated number of apoB particles is present. Therapy to normalize non-HDL-C or, better yet, apoB/LDL-P, is warranted. The clue that residual risk is present even when LDL-C is normal is the reduction of HDL-C and elevation of TG and non-HDL-C.

Dr. Dayspring serves on the advisory board for LipoScience. Dr. Helmbold reports no financial relationships relevant to this article.

Add another item to your ever-growing list of responsibilities: monitoring your patients’ risk of atherosclerosis.

This task used to be the purview of internists and cardiologists but, because gynecologists are increasingly serving as a primary care provider, you need to learn to recognize and diagnose the many clinical expressions of atherosclerosis in your aging patients.

A crucial part of that knowledge is a thorough understanding of each and every lipid concentration parameter reported within the standard lipid profile. This article reviews those parameters, explains how to interpret them individually and in combination, and introduces a new paradigm: the analysis of lipoprotein particle concentrations as a more precise way to determine risk.

If used in its entirety, the lipid profile provides a significant amount of information about the presence or absence of pathologic lipoprotein concentrations. Far too many clinicians focus solely on low-density lipoprotein cholesterol (LDL-C) and ignore the rest of the profile. Failure to consider the other variables is one reason why atherosclerotic disease is underdiagnosed and undertreated in the United States in many patients—especially women.¹

Why lipoproteins are important

There is only one absolute in atherosclerosis: Sterols—predominantly cholesterol—enter the artery wall, where they are oxidized, internalized by macrophages, and transformed into foam cells, the histologic hallmark of atherosclerosis. With the accumulation of foam cells, fatty streaks develop and, ultimately, so does complex plaque.

Lipids associated with cardiovascular disease (CVD) include:

• cholesterol
• noncholesterol sterols such as sitosterol, campesterol, and others of mostly plant or shellfish origin
• triacylglycerol, or triglycerides (TG)
• phospholipids.

Because lipids are insoluble in aqueous solutions such as plasma, they must be “trafficked” within protein-enwrapped particles called lipoproteins. The surface proteins that provide structure and solubility to lipoproteins are called apolipoproteins. A key concept is that, with their surface apolipoproteins and cholesterol core, certain lipoproteins are potential agents of atherogenesis in that they transport sterols into the artery wall.²

Estimation of the risk of CVD involves careful analysis of all standard lipid concentrations and their various ratios, and prediction of the potential presence of atherogenic lipoproteins. Successful prevention or treatment of atherosclerosis entails limiting the presence of atherogenic lipoproteins.

A new paradigm is on its way

The atherogenicity of lipoprotein particles is determined by particle concentration as well as other variables, including particle size, lipid composition, and distinct surface apolipoproteins.

Lipoproteins smaller than 70 nm in diameter are driven into the arterial intima primarily by concentration gradients, regardless of lipid composition or particle size.³ A recent Consensus Statement from the American Diabetes Association and the American College of Cardiology observed that quantitative analysis of these potentially atherogenic lipoproteins is one of the best lipid/lipoprotein-related determinants of CVD risk.⁴ Lipoprotein particle concentrations have emerged not only as superb predictors of risk, but also as goals of therapy.^5-7

Because of cost, third-party reimbursement, varying test availability, and lack of interpretive knowledge, few clinicians routinely order lipoprotein quantification. Historically, CVD risk and goals of therapy have been based on lipid concentrations (the amount of lipids trafficked within lipoprotein cores) reported in the lipid profile. Guidelines from the National Cholesterol Education Program, Adult Treatment Panel III (NCEP ATP-III)^8,9 and the American Heart Association (AHA) CVD Prevention in Women^10,11 use lipid concentrations such as total cholesterol (TC), LDL-C, high-density lipoprotein cholesterol (HDL-C), and TG as estimates or surrogates of lipoprotein concentrations ( TABLE 1 ).

The day is rapidly approaching, however, when lipoprotein concentrations may replace the lipid profile in clinical practice. It is critical that clinicians develop a solid understanding of lipoprotein physiology and pathology.^7,12 It also is crucial that we be as skilled as possible in accurately predicting lipoprotein pathology using all of the lipid concentration parameters present in the lipid panel.

TABLE 1

Desirable lipid values for women

How lipoproteins are analyzed

Lipoproteins can be separated into their components using any of several methodologies, including ultracentrifugation, electrophoresis, apolipoprotein content analysis, and nuclear magnetic resonance (NMR) spectroscopy. Of these, only the last two provide information on particle concentrations.^13,14

Apolipoprotein content analysis reveals two major categories of particles:

• alpha-lipoproteins, or HDL, which contain two to four molecules of apolipoprotein A-I (apoA-I)
• beta-lipoproteins, a collective group of chylomicrons, very-low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), and LDL, each containing a single molecule of apolipoprotein B (apoB). Because of very different half-lives (chylomicrons, 1 hour; VLDL, 2–6 hours; IDL, 1–2 hours; LDL, 2–3 days), the great majority (90% to 95%) of apoB-containing particles are LDL. Although apoB measurement yields quantification of all beta-lipoproteins, it is primarily a surrogate of LDL particle (LDL-P) concentration.¹⁵

Individual particle concentrations, determined by NMR spectroscopy, are reported as VLDL-P, IDL-P, LDL-P, and HDL-P (see the “Glossary”).¹⁴

Several epidemiologic studies that enrolled both genders found the best predictors of risk to be:

• elevated levels of apoB or LDL-P and reduced levels of apoA-I or HDL-P
• a high apoB/apoA-I ratio or LDL-P/HDL-P ratio.^6,13,14

After adjustment for lipoprotein concentration data (apoB or LDL-P), other lipoprotein characteristics such as particle lipid content, size, or composition, for the most part, had no statistically significant relationship with the risk of cardiovascular disease.^16,17

Lipids and lipoproteins: A glossary

Using lipid measurements to estimate lipoproteins

Total cholesterol represents the cholesterol content within all lipoproteins in 1 dL of plasma. Because beta-lipoproteins are considerably larger than alpha-lipoproteins, approximately 75% of total cholesterol is carried in the apoB-containing particles, making TC an apoB surrogate.

VLDL-C, an often ignored variable, is not measured but calculated using the Friedewald formula, dividing TG by five. This calculation assumes—often erroneously as TG levels rise—that TG consists only of VLDL particles and that VLDL composition contains five times more TG than cholesterol molecules.

A desirable TG level is <150 mg/dL, so normal VLDL-C is 150/5 or <30 mg/dL.

LDL-C is also an apoB surrogate

Although VLDL-C is a weak apoB surrogate,¹⁵ data from the Framingham Heart Study showed it to be a good predictor of VLDL remnant particles.¹⁸ However, because the vast majority of beta-lipoproteins are LDL, LDL-C (especially if elevated) is a better apoB surrogate than VLDL-C and is the primary CVD risk factor and goal of therapy in every current guideline.

LDL-C is usually a calculated value using the formula:

LDL-C = TC – (HDL-C + VLDL-C)

Upon special order, laboratories can directly measure LDL-C. This option is most useful when TG levels are high, rendering the Friedewald formula less accurate ( TABLE 2 ).¹⁹ For population cut points and desirable goals of therapy for lipid and lipoprotein concentrations, see the FIGURE .

TABLE 2

How lipid concentrations are determined

FIGURE Population percentile cut points and goals for LDL-C, LDL-P, ApoB, and non-HDL-C

HDL-C, apoA-I are inversely related to cardiovascular risk

The epidemiologic data strongly indicate that both HDL-C and apoA-I are strongly and inversely related to CVD risk.⁶ HDL particles are a heterogenous collection of:

• unlipidated apoA-I
• very small pre-beta HDL
• more mature, lipidated HDL3 and HDL2 species (HDL3 smaller than HDL2).

NMR nomenclature identifies the smaller HDL species as H1 and H2 and the larger HDL species as H4 and H5.¹⁴ The smaller HDL species also contain apoA-II.

Although HDL can acquire cholesterol from any cell, including arterial-wall foam cells, the majority of HDL lipidation occurs in the liver or proximal small intestine, after which it is trafficked to steroidogenic tissue, adipocytes, or back to the liver. Normally, HDL carries little TG.²⁰ The only lipid concentration that can serve as a surrogate of apoA-I or HDL-P is HDL-C, where the assumption is that higher HDL-C indicates higher apoA-I, and vice versa.

In reality, the correlation between apoA-I and HDL-C varies because each HDL particle can have from two to four apoA-I molecules, and the volume of cholesterol within the particle is a function of particle size and its TG content. For the most part, total HDL-C is indicative of the cholesterol carried in the larger, mature HDL2 (H4, H5) particles; patients with low HDL-C typically lack these mature, lipidated HDL particles.

Because HDL rapidly and repeatedly lipidates and then delipidates, there is no relationship between the HDL-C level and the complex dynamic process termed reverse cholesterol transport process. Neither HDL-C, nor apoA-I, nor HDL-P, nor HDL size is consistently related to HDL particle functionality—i.e., the ability of HDL to lipidate or delipidate, appropriately traffic cholesterol, or perform numerous other nonlipid antiatherogenic functions.^20,21

Focus on lipoprotein particle concentrations

To most accurately predict lipid-related CVD risk, you must determine which patients have elevated numbers of atherogenic lipoproteins using actual particle concentrations. In most practices, lipoprotein particle numbers must be estimated by scrutinizing all of the lipid concentrations and ratios (not simply LDL-C).

TC and, especially, LDL-C are apoB and LDL-P surrogates, but the best lipid concentration estimate of apoB is the calculated non-HDL-C value. By subtracting HDL-C from TC, it is possible to identify the cholesterol not in the HDL particles but in all of the potentially atherogenic apoB particles. In essence, non-HDL-C is VLDL-C plus LDL-C. This equation yields a better apoB or LDL-P proxy, compared with LDL-C alone.¹⁸ If a patient has reached her LDL-C goal but still has a high non-HDL-C level, we can assume that there are still too many apoB particles and that they are contributing to residual risk.

Because LDL is the predominant apoB species, non-HDL-C is the best lipid concentration predictor of LDL-P.¹⁵ Because neither TC nor HDL-C assays require a patient to fast, non-HDL-C is accurate in nonfasting patients, making it a very practical way to screen for CVD risk.⁸ In the Women’s Health Study, which involved mostly healthy women, non-HDL-C predicted the risk of coronary heart disease as well as apoB did, but not as well as LDL-P.^22,23 In independent, separately published analyses from the Framingham Off-spring Study, LDL-P was a better predictor of risk than LDL-C and apoB.^15,24

NCEP ATP-III guidelines introduced non-HDL-C as a secondary goal of therapy in patients with TG >200 mg/dL. Subsequent data indicate that non-HDL-C is always a better predictor of risk than LDL-C is, regardless of TG levels.¹⁸

The AHA Women’s Guideline was the first to set a desired non-HDL-C level (130 mg/dL) independent of the TG value.¹⁰ Because a normal VLDL-C concentration is 30 mg/dL, the non-HDL-C goal is 30 mg/dL above the desired LDL-C goal. For example, if the desired LDL-C value is 100 mg/dL, the non-HDL-C goal is 130 mg/dL. If the desired LDL-C goal is 70 mg/dL—as it is in a patient at very high risk—the non-HDL-C goal would be 100 mg/dL ( FIGURE ).^9,11

Insulin resistance diminishes accuracy of lipid profile

The ability to predict lipoprotein particle concentrations using the lipid profile becomes far less accurate in situations associated with insulin resistance and metabolic syndrome in patients who have TG-HDL axis disorders. In women, these disorders are typified by an elevation of TG >150 mg/dL and a decrease in HDL-C <50 mg/dL, with borderline or normal LDL-C levels.²⁵

As TG begins to rise above 120 mg/dL, hepatic secretion of TG-rich VLDL particles increases. As VLDL-TG is hydrolyzed by lipoprotein lipase in muscle and fat cells, in a process termed lipolysis, VLDL shrinks and transforms into IDL. Ultimately, unless it is cleared by hepatic LDL receptors, the IDL undergoes additional lipolysis by hepatic lipase and transforms into LDL particles. Because of their longer half-life, these LDL particles accumulate, further elevating apoB and LDL-P.

In the presence of TG-rich VLDL and chylomicrons, additional pathologic particle remodeling occurs. By way of a lipid transfer protein called cholesteryl ester transfer protein (CETP), some of the TG molecules present in TG-rich lipoproteins are exchanged for cholesteryl esters in LDL and HDL. This lipid transfer creates LDL and HDL that are TG-rich and cholesterol-poor, enabling additional TG lipolysis by hepatic lipase to create smaller LDL and HDL. The latter is so small that it can pass through renal glomeruli and be excreted, leading to reductions of HDL-P, apoA-I, and HDL-C.

Also created in this process are smaller, atherogenic, cholesterol-rich VLDL and chylomicron remnants, diagnosable by an elevated VLDL-C. Patients who have this pathology typically have elevated TG, reduced HDL-C, variable LDL-C, and an increased TG/HDL-C ratio (>3.8), which are indicative of too many small LDL particles (high apoB, LDL-P) and reduced number of HDL particles (high apoB/A-I ratio).^26,27

Such a scenario, typical of TG-HDL axis disorders, explains much of the risk associated with rising TG levels and is very common in premenopausal women who have insulin-resistant states such as type 2 diabetes or polycystic ovary syndrome and in menopausal women who have insulin resistance and coronary artery disease.¹

LDL-C and LDL-P do not always correlate

Because the volume of a lipoprotein is a function of its radius cubed (V = 4/3πr³),¹⁴ a patient who has small LDL will require up to 40% to 70% more LDL particles to traffic a given amount of LDL-C. In such a patient, there is often little correlation between LDL-C and LDL-P or apoB values. Regardless of the LDL-C, the apoB, LDL-P, or non-HDL-C is often elevated.²⁸ This risk, which cannot be predicted by looking only at LDL-C, is the main reason guidelines advocate the use of non-HDL-C or the TC/HDL-C ratio.^8,11 (See the case studies.)

In summary, a large part of the risk of CVD seen in patients who have low HDL-C derives from the associated increase in the number of apoB particles, mostly composed of small LDL, as well as an increase in remnant particles.^15,21,28 This crucial point explains why treatment of low HDL-C states should always first target apoB or LDL-P (LDL-C and non-HDL-C), rather than apoA-I or HDL-C ( TABLES 3 and 4 ).^8,9

TABLE 3

Lipid markers of small low-density lipoproteins

TABLE 4

Lipid markers of remnant lipoproteins

A few words of advice

The driving forces of atherogenesis are increased numbers of apoB-containing lipoproteins and impaired endothelial integrity. ApoB and LDL-P are the available lab assays that most accurately quantify atherogenic particle number.

The lipid-concentration surrogates that you should be using to better predict apoB and CVD risk are:

• TC (unless HDL-C is very high)
• LDL-C
• Non-HDL-C
• TC/HDL-C ratio
• TG/HDL-C ratio.

Because LDL is by far the most numerous of the apoB particles present in plasma, it is the primary agent of atherogenesis. However, apoB and LDL-P do not correlate with LDL-C when LDL particles are small, are TG-rich and cholesterol-poor, or simply cholesterol-poor (seen in some patients who have low LDL-C levels).^7,15

Both NCEP ATP-III and AHA Women’s Guidelines use the TC/HDL ratio as a powerful risk predictor. However, as a goal of therapy, these guidelines recommend normalizing LDL-C and then non-HDL-C.^8,11 In reality, normalization of non-HDL-C takes care of LDL-C as well. For example, say a patient has LDL-C <100 mg/dL, but non-HDL-C >130 mg/dL or TC/HDL-C ratio >4. These readings indicate residual risk and suggest that an elevated number of apoB particles is present. Therapy to normalize non-HDL-C or, better yet, apoB/LDL-P, is warranted. The clue that residual risk is present even when LDL-C is normal is the reduction of HDL-C and elevation of TG and non-HDL-C.

Dr. Weinstein has no financial relationships relevant to this article.

“I CAN’T GET NO SATISFACTION”—Mick Jagger and Keith Richards, 1965

“FOR THE TIMES THEY ARE A-CHANGIN’”—Bob Dylan, 1964

The lyrics of two songs written more than 40 years ago are an excellent way to describe today’s physician workforce. Regrettably, many physicians who grew up listening to these performer-philosophers have yet to heed the words of Bob Dylan. Instead, they echo the sentiments of Mick Jagger and Keith Richards without doing much to correct the problem.

Why the decline in work satisfaction? Many reasons have been cited, including:

• loss of autonomy
• economic pressures
• an increasing degree of government and insurer control over practice
• the liability crisis
• a divergence between professional and personal expectations
• physicians’ own high career expectations
• a desire for more time for family and self.¹

The growing level of dissatisfaction with the practice of medicine has, clearly, reached crisis level: Twenty percent of all physicians report that they are dissatisfied with their career.^2,3 And lack of fulfillment appears to be developing much earlier in the life of a physician than has so far been appreciated. Not only is it showing up in residents, job dissatisfaction is evident even among medical students. It is quite revealing—and depressing—that 40% of young physicians would choose not to go to medical school if they had to choose again.

In this article, I examine the characteristics of the dissatisfied physician, explain the apparent reasons for this lack of fulfillment, and propose a number of steps that can be taken to salvage the situation, lengthen the time that a physician works, on average, and add flexibility and variety to work life.

Ultimate effect of dissatisfaction? Loss of a physician

An unhappy physician is two or three times more likely to leave the profession or decrease the number of hours worked than a satisfied physician is.⁴ And when a physician leaves the workforce, we lose a valuable resource. The estimated replacement cost for a physician in 1992 to 1999 dollars was $250,000, and that cost is at least 50% higher today.^5,6 Besides the monetary loss, there is disruption to other members of the practice group and to patients when a physician leaves the profession.

Landon and colleagues found that the average age of a physician working full-time was 47 years, compared with 53 years for a physician who was working fewer than 20 hours a week and 63 years for a physician at retirement.⁴ However, these data are approximately 7 years old; current figures are likely to show curtailment of work hours at even younger ages.

It is not realistic to expect that 1) the educational system will increase medical school class size and 2) enough physicians will finish training and develop a mature practice in the time necessary to offset the number of physicians now altering their workloads or exiting the workforce.

Does gender influence the satisfaction rate?

The profession of medicine has changed strikingly over the past 20 years. Once male-dominated, it now is gender-equal and, in some specialties, female-dominated.

This rapid gender shift in medicine has received much of the blame for the decline in physician satisfaction. However, data suggest that, among full-time academic faculty who do not have children, productivity and career satisfaction are the same for women as for men.⁷ A recent study of internists found few gender differences in work-life balance, work hours, and attitudes toward patient care.⁸

Among surgeons, an equal percentage of each gender believes that the work schedule leaves too little time for personal and family life.⁹ Although it has been suggested that women prefer to work fewer hours than men, evidence indicates that younger men have the same desire to work less and spend more time with family.¹⁰

That said, there are some gender-related differences in medical workforce characteristics:

• Women reduce their clinical activity during childbearing and childrearing and retire 5.5 years earlier than men do⁴
• In obstetrics, women younger than 40 years are four times more likely to reduce work hours or completely stop practice than male obstetricians are¹¹
• Among surgeons, 90% of women live in dual-career households, compared with 50% of men⁹
• When the surgeon is male, children are cared for by spouses in 63% of households; when the surgeon is female, children are cared for by an employee in 88% of households⁹
• Among surgical subspecialists, women are more likely to be divorced or separated and to have fewer or no children; 34% spend 21 to 40 hours weekly on household management.¹²

Despite these differences, a review of the literature on physician dissatisfaction suggests that the gender shift in medicine is not responsible for the growing level of dissatisfaction.

Age is the determining factor

The Baby Boomer generation (born between 1946 and 1964), which had largely controlled all aspects of medicine, especially leadership roles, is rapidly being replaced by physicians from Generations X and Y (born between 1965 and 1980, and 1981 and 2001, respectively), who value personal time and lifestyle much more than “Boomers” have.¹³

These younger physicians demand flexibility and variety in their careers. They grow dissatisfied when these aspects of their work lives fall out of their control. And when it comes to choosing a specialty in which to practice, these physicians see a balanced lifestyle as the key variable.¹³

Much of the discussion of dissatisfaction in medicine has contrasted Baby Boomers with subsequent generations. The Boomer physician typically has a traditional marriage, with the spouse doing most of the parenting and managing household duties. The Boomer physician is more likely to be male, work long hours, and see professional life as the overall driving force of daily existence.

However, the perception that a Boomer physician is immune to career dissatisfaction is incorrect. Dissatisfaction and departure from practice are directly related to age, with those who are 50 or older more likely to experience them.¹⁴ In another study, age and dissatisfaction were the principal factors positively associated with intention to leave practice.¹⁵

For Generations X and Y, time is the overarching issue

Generations X and Y physicians are an equal mix of genders, with the majority of couples having dual careers. Their desire for balanced work and family life has made time the primary issue in rising dissatisfaction with medicine. There is less time for each patient encounter, more time required for documentation to justify reimbursement, more time necessary to deal with practice management, and less time to handle family issues—especially personal well-being.¹⁶ These issues have also contributed to rising dissatisfaction among Baby Boomers.

Enter, the 80-hour workweek

In 2003, the Accreditation Council for Graduate Medical Education instituted the 80-hour workweek in an attempt to improve patient safety and the lifestyle of physicians in training. Many senior physicians believed that work-hour restriction would erode the quality of training, but this does not appear to have occurred.

Work-hour restriction among surgical residents has had no effect on academic performance but has markedly decreased psychological distress.¹⁷ Among medical residents, work-hour restriction has improved career satisfaction and decreased emotional exhaustion—but residents perceive restrictions to have impinged on patient care and resident education.¹⁸ Although surgical residents believe that restriction has reduced overall stress, improved quality of life, and provided time in which to manage their personal life, they are concerned about the limitation on exposure to patients—yet 96% of these residents would not be willing to add an additional year to their training.¹⁹

There is evidence that about one third of a resident’s time is spent performing activities of marginal or no educational value.²⁰ By eliminating these activities and making better use of simulators and patient surrogates, the workweek could be reduced even further, allowing the physician in training more time for interaction with patients and providing a better balance between work and personal life.

Burnout is widespread

If the goal is to retain physicians in the work-force, it is more important to reduce dissatisfaction than to increase satisfaction. Why? People who are dissatisfied are more likely to change what they are doing than those with any level of satisfaction.⁴

The profession must understand that burnout is common and directly related to increasing dissatisfaction.²¹

Burnout typically occurs when one has a highly demanding position with limited autonomy. A physician experiences burnout when one or more of the following is present:

• emotional exhaustion
• feelings of inadequacy in terms of personal accomplishment
• depersonalization
• increasing cynicism in personal interactions.²¹

This is an accurate description of the current state of medical practice.

Because “the times they are a-changin’,” it is necessary that leaders within the medical profession drastically change the way that medicine is taught and practiced.^22-24

Any further changes—beyond work-hour limitations—should be carefully designed with a mechanism in place to evaluate effects on both physicians and patients. A new approach to the practice of medicine is desperately needed to allow a better work-life balance while maintaining the focus on quality and safety.

Ways to reduce dissatisfaction

Dr. Abigail Zuger summed up the feelings of many when she wrote: “The profession of medicine has taken its members on a wild ride during the past century: a slow, glorious climb in well-being, followed by a steep, stomach-churning fall.”²⁵

I offer the following proposals for discussion. My primary aim in developing these suggestions was to give physicians more of that most precious of commodities: time. More time has the potential to change the work-life balance and improve both professional and personal satisfaction at the same time that it decreases dissatisfaction.

Again: The key to retaining physicians in the workforce is to decrease dissatisfaction. That is more likely to have the desired effect of a larger, stable workforce than is increasing the number of medical students and physicians in training. As is true in most aspects of life, it is easier and cheaper to improve what you already have, recycle what you can, and replace only what is absolutely necessary.

Recommendations—for practitioners, academic and private

• Limit work hours to 50 or fewer per week. Many physicians work too many hours; this is not beneficial to them, their families, and their patients.²⁶ For both patient safety and physician well-being, it is time to voluntarily restrict our work hours before federal legislation creates limits for us.
• Develop new models of practice, such as the use of a laborist for obstetric coverage. The implementation of a hospital-based laborist program allows a safer environment for the patient, a rapid-response team presence, and a controlled lifestyle for physicians who desire to practice obstetrics.²⁷ Structured properly, such models are revenue-neutral for the institution. (See OBG Management’s recent article, “The laborists are here, but can they thrive in US hospitals?” in the August 2008 issue, available at www.obgmanagement.com.)
• Create part-time professional liability insurance policies. Premiums for these policies should be prorated according to the amount of clinical time worked and the physician’s work record. Insurance policies also need to be written to cover a slot rather than a particular individual, so that several physicians can share the same position to equal one full-time practitioner.
• Increase job sharing and part-time employment so that these options become more attractive. With job sharing, two physicians work 50% of the time, adding up to one full-time practitioner. This option will reduce physician dissatisfaction and has the potential to increase the work life of the practitioner while improving patient safety.²⁸ Job sharing will also facilitate recruitment and retention of the current workforce.²⁹
• Acquire time- and money-management skills. Most practitioners need to develop these abilities because so many stressors are related to limits on time and money.
• In academic medicine, revamp the current career trajectory. The timeline that includes tenure and unrealistic expectations for promotion is archaic and needs to be eliminated. Most Generations X and Y physicians find it to be inflexible at exactly the wrong time in their life. Forced to choose between work on one hand and family and personal well-being on the other, they will almost always choose family and personal life first.³⁰ Similar changes are recommended for the private practitioner under consideration for partnership.

Recommendations—for physicians in training

• Limit work hours to 65 or fewer per week. The current 80-hour week is not conducive to improving physician satisfaction or safe care. There is evidence that work exceeding 18 hours a day may impair a physician.³¹ No physician likes working long hours, and it is clearly not safe for patients. Elimination of responsibilities of no or marginal educational value would make a 65-hour work-week practical. Training institutions will need to add more support staff, including physician extenders, to implement a shorter week.
• Increase the use of teaching simulators. This improvement would assist in the development of technical skills. The training institution would be responsible for developing a simulation center. In areas with multiple training programs, a central location would be developed, with cost shared by all parties. Some of the cost would be recouped by the time saved in the operating room. There is also the potential to prevent medical errors and reduce liability cost. (See OBG Management’s recent article, “How simulation can train, and refresh, physicians for critical OB events,” which describes, among other issues, the use of regional simulation centers. The article appeared in the September 2008 issue, available at www.obgmanagement.com.)
• Teach physicians in training time- and money-management skills. Many of the stressors experienced by these young physicians relate to understanding how to budget time and money.
• Sponsor 24-hour, on-site child care at reasonable or no cost. This recommendation for the training institution is important because child care for the dual-career couple is difficult to arrange, often incompatible with the couple’s schedule, and expensive. Any training institution that sponsors a residency program and benefits from this low-cost workforce should be required by the Accreditation Council of Graduate Medical Education to fund this benefit. It is the right thing to do and is certainly a valuable recruiting tool. It will make physicians who have children feel more comfortable working the hours required for their training while removing a major stressor—worrying about their child.
• Supply extra support for residents when a co-resident is on maternity or paternity leave. The training institution should implement this protection to prevent working residents from being penalized when it is necessary for a co-resident to be on leave.
• Create the option of job sharing during residency. In the business world, job sharing has become common and increases satisfaction and productivity. A resident would work half-time, with salary and benefits prorated so that the cost to the sponsoring institution is revenue-neutral. This would be a valuable recruiting tool among residents who are willing to accept a prolonged period of training.

We need a dialogue on these and other recommendations Such a conversation will allow the medical profession to continue to attract and retain the best and brightest professionals. As the satirical poet Auguste Marseille Barthélemy pointed out, way back in 1832: “The absurd man is he who never changes.”

Dr. Weinstein has no financial relationships relevant to this article.

“I CAN’T GET NO SATISFACTION”—Mick Jagger and Keith Richards, 1965

“FOR THE TIMES THEY ARE A-CHANGIN’”—Bob Dylan, 1964

The lyrics of two songs written more than 40 years ago are an excellent way to describe today’s physician workforce. Regrettably, many physicians who grew up listening to these performer-philosophers have yet to heed the words of Bob Dylan. Instead, they echo the sentiments of Mick Jagger and Keith Richards without doing much to correct the problem.

Why the decline in work satisfaction? Many reasons have been cited, including:

• loss of autonomy
• economic pressures
• an increasing degree of government and insurer control over practice
• the liability crisis
• a divergence between professional and personal expectations
• physicians’ own high career expectations
• a desire for more time for family and self.¹

The growing level of dissatisfaction with the practice of medicine has, clearly, reached crisis level: Twenty percent of all physicians report that they are dissatisfied with their career.^2,3 And lack of fulfillment appears to be developing much earlier in the life of a physician than has so far been appreciated. Not only is it showing up in residents, job dissatisfaction is evident even among medical students. It is quite revealing—and depressing—that 40% of young physicians would choose not to go to medical school if they had to choose again.

In this article, I examine the characteristics of the dissatisfied physician, explain the apparent reasons for this lack of fulfillment, and propose a number of steps that can be taken to salvage the situation, lengthen the time that a physician works, on average, and add flexibility and variety to work life.

Ultimate effect of dissatisfaction? Loss of a physician

An unhappy physician is two or three times more likely to leave the profession or decrease the number of hours worked than a satisfied physician is.⁴ And when a physician leaves the workforce, we lose a valuable resource. The estimated replacement cost for a physician in 1992 to 1999 dollars was $250,000, and that cost is at least 50% higher today.^5,6 Besides the monetary loss, there is disruption to other members of the practice group and to patients when a physician leaves the profession.

Landon and colleagues found that the average age of a physician working full-time was 47 years, compared with 53 years for a physician who was working fewer than 20 hours a week and 63 years for a physician at retirement.⁴ However, these data are approximately 7 years old; current figures are likely to show curtailment of work hours at even younger ages.

It is not realistic to expect that 1) the educational system will increase medical school class size and 2) enough physicians will finish training and develop a mature practice in the time necessary to offset the number of physicians now altering their workloads or exiting the workforce.

Does gender influence the satisfaction rate?

The profession of medicine has changed strikingly over the past 20 years. Once male-dominated, it now is gender-equal and, in some specialties, female-dominated.

This rapid gender shift in medicine has received much of the blame for the decline in physician satisfaction. However, data suggest that, among full-time academic faculty who do not have children, productivity and career satisfaction are the same for women as for men.⁷ A recent study of internists found few gender differences in work-life balance, work hours, and attitudes toward patient care.⁸

Among surgeons, an equal percentage of each gender believes that the work schedule leaves too little time for personal and family life.⁹ Although it has been suggested that women prefer to work fewer hours than men, evidence indicates that younger men have the same desire to work less and spend more time with family.¹⁰

That said, there are some gender-related differences in medical workforce characteristics:

• Women reduce their clinical activity during childbearing and childrearing and retire 5.5 years earlier than men do⁴
• In obstetrics, women younger than 40 years are four times more likely to reduce work hours or completely stop practice than male obstetricians are¹¹
• Among surgeons, 90% of women live in dual-career households, compared with 50% of men⁹
• When the surgeon is male, children are cared for by spouses in 63% of households; when the surgeon is female, children are cared for by an employee in 88% of households⁹
• Among surgical subspecialists, women are more likely to be divorced or separated and to have fewer or no children; 34% spend 21 to 40 hours weekly on household management.¹²

Despite these differences, a review of the literature on physician dissatisfaction suggests that the gender shift in medicine is not responsible for the growing level of dissatisfaction.

Age is the determining factor

The Baby Boomer generation (born between 1946 and 1964), which had largely controlled all aspects of medicine, especially leadership roles, is rapidly being replaced by physicians from Generations X and Y (born between 1965 and 1980, and 1981 and 2001, respectively), who value personal time and lifestyle much more than “Boomers” have.¹³

These younger physicians demand flexibility and variety in their careers. They grow dissatisfied when these aspects of their work lives fall out of their control. And when it comes to choosing a specialty in which to practice, these physicians see a balanced lifestyle as the key variable.¹³

Much of the discussion of dissatisfaction in medicine has contrasted Baby Boomers with subsequent generations. The Boomer physician typically has a traditional marriage, with the spouse doing most of the parenting and managing household duties. The Boomer physician is more likely to be male, work long hours, and see professional life as the overall driving force of daily existence.

However, the perception that a Boomer physician is immune to career dissatisfaction is incorrect. Dissatisfaction and departure from practice are directly related to age, with those who are 50 or older more likely to experience them.¹⁴ In another study, age and dissatisfaction were the principal factors positively associated with intention to leave practice.¹⁵

For Generations X and Y, time is the overarching issue

Generations X and Y physicians are an equal mix of genders, with the majority of couples having dual careers. Their desire for balanced work and family life has made time the primary issue in rising dissatisfaction with medicine. There is less time for each patient encounter, more time required for documentation to justify reimbursement, more time necessary to deal with practice management, and less time to handle family issues—especially personal well-being.¹⁶ These issues have also contributed to rising dissatisfaction among Baby Boomers.

Enter, the 80-hour workweek

In 2003, the Accreditation Council for Graduate Medical Education instituted the 80-hour workweek in an attempt to improve patient safety and the lifestyle of physicians in training. Many senior physicians believed that work-hour restriction would erode the quality of training, but this does not appear to have occurred.

Work-hour restriction among surgical residents has had no effect on academic performance but has markedly decreased psychological distress.¹⁷ Among medical residents, work-hour restriction has improved career satisfaction and decreased emotional exhaustion—but residents perceive restrictions to have impinged on patient care and resident education.¹⁸ Although surgical residents believe that restriction has reduced overall stress, improved quality of life, and provided time in which to manage their personal life, they are concerned about the limitation on exposure to patients—yet 96% of these residents would not be willing to add an additional year to their training.¹⁹

There is evidence that about one third of a resident’s time is spent performing activities of marginal or no educational value.²⁰ By eliminating these activities and making better use of simulators and patient surrogates, the workweek could be reduced even further, allowing the physician in training more time for interaction with patients and providing a better balance between work and personal life.

Burnout is widespread

If the goal is to retain physicians in the work-force, it is more important to reduce dissatisfaction than to increase satisfaction. Why? People who are dissatisfied are more likely to change what they are doing than those with any level of satisfaction.⁴

The profession must understand that burnout is common and directly related to increasing dissatisfaction.²¹

Burnout typically occurs when one has a highly demanding position with limited autonomy. A physician experiences burnout when one or more of the following is present:

• emotional exhaustion
• feelings of inadequacy in terms of personal accomplishment
• depersonalization
• increasing cynicism in personal interactions.²¹

This is an accurate description of the current state of medical practice.

Because “the times they are a-changin’,” it is necessary that leaders within the medical profession drastically change the way that medicine is taught and practiced.^22-24

Any further changes—beyond work-hour limitations—should be carefully designed with a mechanism in place to evaluate effects on both physicians and patients. A new approach to the practice of medicine is desperately needed to allow a better work-life balance while maintaining the focus on quality and safety.

Ways to reduce dissatisfaction

Dr. Abigail Zuger summed up the feelings of many when she wrote: “The profession of medicine has taken its members on a wild ride during the past century: a slow, glorious climb in well-being, followed by a steep, stomach-churning fall.”²⁵

I offer the following proposals for discussion. My primary aim in developing these suggestions was to give physicians more of that most precious of commodities: time. More time has the potential to change the work-life balance and improve both professional and personal satisfaction at the same time that it decreases dissatisfaction.

Again: The key to retaining physicians in the workforce is to decrease dissatisfaction. That is more likely to have the desired effect of a larger, stable workforce than is increasing the number of medical students and physicians in training. As is true in most aspects of life, it is easier and cheaper to improve what you already have, recycle what you can, and replace only what is absolutely necessary.

Recommendations—for practitioners, academic and private

• Limit work hours to 50 or fewer per week. Many physicians work too many hours; this is not beneficial to them, their families, and their patients.²⁶ For both patient safety and physician well-being, it is time to voluntarily restrict our work hours before federal legislation creates limits for us.
• Develop new models of practice, such as the use of a laborist for obstetric coverage. The implementation of a hospital-based laborist program allows a safer environment for the patient, a rapid-response team presence, and a controlled lifestyle for physicians who desire to practice obstetrics.²⁷ Structured properly, such models are revenue-neutral for the institution. (See OBG Management’s recent article, “The laborists are here, but can they thrive in US hospitals?” in the August 2008 issue, available at www.obgmanagement.com.)
• Create part-time professional liability insurance policies. Premiums for these policies should be prorated according to the amount of clinical time worked and the physician’s work record. Insurance policies also need to be written to cover a slot rather than a particular individual, so that several physicians can share the same position to equal one full-time practitioner.
• Increase job sharing and part-time employment so that these options become more attractive. With job sharing, two physicians work 50% of the time, adding up to one full-time practitioner. This option will reduce physician dissatisfaction and has the potential to increase the work life of the practitioner while improving patient safety.²⁸ Job sharing will also facilitate recruitment and retention of the current workforce.²⁹
• Acquire time- and money-management skills. Most practitioners need to develop these abilities because so many stressors are related to limits on time and money.
• In academic medicine, revamp the current career trajectory. The timeline that includes tenure and unrealistic expectations for promotion is archaic and needs to be eliminated. Most Generations X and Y physicians find it to be inflexible at exactly the wrong time in their life. Forced to choose between work on one hand and family and personal well-being on the other, they will almost always choose family and personal life first.³⁰ Similar changes are recommended for the private practitioner under consideration for partnership.

Recommendations—for physicians in training

• Limit work hours to 65 or fewer per week. The current 80-hour week is not conducive to improving physician satisfaction or safe care. There is evidence that work exceeding 18 hours a day may impair a physician.³¹ No physician likes working long hours, and it is clearly not safe for patients. Elimination of responsibilities of no or marginal educational value would make a 65-hour work-week practical. Training institutions will need to add more support staff, including physician extenders, to implement a shorter week.
• Increase the use of teaching simulators. This improvement would assist in the development of technical skills. The training institution would be responsible for developing a simulation center. In areas with multiple training programs, a central location would be developed, with cost shared by all parties. Some of the cost would be recouped by the time saved in the operating room. There is also the potential to prevent medical errors and reduce liability cost. (See OBG Management’s recent article, “How simulation can train, and refresh, physicians for critical OB events,” which describes, among other issues, the use of regional simulation centers. The article appeared in the September 2008 issue, available at www.obgmanagement.com.)
• Teach physicians in training time- and money-management skills. Many of the stressors experienced by these young physicians relate to understanding how to budget time and money.
• Sponsor 24-hour, on-site child care at reasonable or no cost. This recommendation for the training institution is important because child care for the dual-career couple is difficult to arrange, often incompatible with the couple’s schedule, and expensive. Any training institution that sponsors a residency program and benefits from this low-cost workforce should be required by the Accreditation Council of Graduate Medical Education to fund this benefit. It is the right thing to do and is certainly a valuable recruiting tool. It will make physicians who have children feel more comfortable working the hours required for their training while removing a major stressor—worrying about their child.
• Supply extra support for residents when a co-resident is on maternity or paternity leave. The training institution should implement this protection to prevent working residents from being penalized when it is necessary for a co-resident to be on leave.
• Create the option of job sharing during residency. In the business world, job sharing has become common and increases satisfaction and productivity. A resident would work half-time, with salary and benefits prorated so that the cost to the sponsoring institution is revenue-neutral. This would be a valuable recruiting tool among residents who are willing to accept a prolonged period of training.

We need a dialogue on these and other recommendations Such a conversation will allow the medical profession to continue to attract and retain the best and brightest professionals. As the satirical poet Auguste Marseille Barthélemy pointed out, way back in 1832: “The absurd man is he who never changes.”

Dr. Weinstein has no financial relationships relevant to this article.

“I CAN’T GET NO SATISFACTION”—Mick Jagger and Keith Richards, 1965

“FOR THE TIMES THEY ARE A-CHANGIN’”—Bob Dylan, 1964

The lyrics of two songs written more than 40 years ago are an excellent way to describe today’s physician workforce. Regrettably, many physicians who grew up listening to these performer-philosophers have yet to heed the words of Bob Dylan. Instead, they echo the sentiments of Mick Jagger and Keith Richards without doing much to correct the problem.

Why the decline in work satisfaction? Many reasons have been cited, including:

• loss of autonomy
• economic pressures
• an increasing degree of government and insurer control over practice
• the liability crisis
• a divergence between professional and personal expectations
• physicians’ own high career expectations
• a desire for more time for family and self.¹

The growing level of dissatisfaction with the practice of medicine has, clearly, reached crisis level: Twenty percent of all physicians report that they are dissatisfied with their career.^2,3 And lack of fulfillment appears to be developing much earlier in the life of a physician than has so far been appreciated. Not only is it showing up in residents, job dissatisfaction is evident even among medical students. It is quite revealing—and depressing—that 40% of young physicians would choose not to go to medical school if they had to choose again.

In this article, I examine the characteristics of the dissatisfied physician, explain the apparent reasons for this lack of fulfillment, and propose a number of steps that can be taken to salvage the situation, lengthen the time that a physician works, on average, and add flexibility and variety to work life.

Ultimate effect of dissatisfaction? Loss of a physician

An unhappy physician is two or three times more likely to leave the profession or decrease the number of hours worked than a satisfied physician is.⁴ And when a physician leaves the workforce, we lose a valuable resource. The estimated replacement cost for a physician in 1992 to 1999 dollars was $250,000, and that cost is at least 50% higher today.^5,6 Besides the monetary loss, there is disruption to other members of the practice group and to patients when a physician leaves the profession.

Landon and colleagues found that the average age of a physician working full-time was 47 years, compared with 53 years for a physician who was working fewer than 20 hours a week and 63 years for a physician at retirement.⁴ However, these data are approximately 7 years old; current figures are likely to show curtailment of work hours at even younger ages.

It is not realistic to expect that 1) the educational system will increase medical school class size and 2) enough physicians will finish training and develop a mature practice in the time necessary to offset the number of physicians now altering their workloads or exiting the workforce.

Does gender influence the satisfaction rate?

The profession of medicine has changed strikingly over the past 20 years. Once male-dominated, it now is gender-equal and, in some specialties, female-dominated.

This rapid gender shift in medicine has received much of the blame for the decline in physician satisfaction. However, data suggest that, among full-time academic faculty who do not have children, productivity and career satisfaction are the same for women as for men.⁷ A recent study of internists found few gender differences in work-life balance, work hours, and attitudes toward patient care.⁸

Among surgeons, an equal percentage of each gender believes that the work schedule leaves too little time for personal and family life.⁹ Although it has been suggested that women prefer to work fewer hours than men, evidence indicates that younger men have the same desire to work less and spend more time with family.¹⁰

That said, there are some gender-related differences in medical workforce characteristics:

• Women reduce their clinical activity during childbearing and childrearing and retire 5.5 years earlier than men do⁴
• In obstetrics, women younger than 40 years are four times more likely to reduce work hours or completely stop practice than male obstetricians are¹¹
• Among surgeons, 90% of women live in dual-career households, compared with 50% of men⁹
• When the surgeon is male, children are cared for by spouses in 63% of households; when the surgeon is female, children are cared for by an employee in 88% of households⁹
• Among surgical subspecialists, women are more likely to be divorced or separated and to have fewer or no children; 34% spend 21 to 40 hours weekly on household management.¹²

Despite these differences, a review of the literature on physician dissatisfaction suggests that the gender shift in medicine is not responsible for the growing level of dissatisfaction.

Age is the determining factor

The Baby Boomer generation (born between 1946 and 1964), which had largely controlled all aspects of medicine, especially leadership roles, is rapidly being replaced by physicians from Generations X and Y (born between 1965 and 1980, and 1981 and 2001, respectively), who value personal time and lifestyle much more than “Boomers” have.¹³

These younger physicians demand flexibility and variety in their careers. They grow dissatisfied when these aspects of their work lives fall out of their control. And when it comes to choosing a specialty in which to practice, these physicians see a balanced lifestyle as the key variable.¹³

Much of the discussion of dissatisfaction in medicine has contrasted Baby Boomers with subsequent generations. The Boomer physician typically has a traditional marriage, with the spouse doing most of the parenting and managing household duties. The Boomer physician is more likely to be male, work long hours, and see professional life as the overall driving force of daily existence.

However, the perception that a Boomer physician is immune to career dissatisfaction is incorrect. Dissatisfaction and departure from practice are directly related to age, with those who are 50 or older more likely to experience them.¹⁴ In another study, age and dissatisfaction were the principal factors positively associated with intention to leave practice.¹⁵

For Generations X and Y, time is the overarching issue

Generations X and Y physicians are an equal mix of genders, with the majority of couples having dual careers. Their desire for balanced work and family life has made time the primary issue in rising dissatisfaction with medicine. There is less time for each patient encounter, more time required for documentation to justify reimbursement, more time necessary to deal with practice management, and less time to handle family issues—especially personal well-being.¹⁶ These issues have also contributed to rising dissatisfaction among Baby Boomers.

Enter, the 80-hour workweek

In 2003, the Accreditation Council for Graduate Medical Education instituted the 80-hour workweek in an attempt to improve patient safety and the lifestyle of physicians in training. Many senior physicians believed that work-hour restriction would erode the quality of training, but this does not appear to have occurred.

Work-hour restriction among surgical residents has had no effect on academic performance but has markedly decreased psychological distress.¹⁷ Among medical residents, work-hour restriction has improved career satisfaction and decreased emotional exhaustion—but residents perceive restrictions to have impinged on patient care and resident education.¹⁸ Although surgical residents believe that restriction has reduced overall stress, improved quality of life, and provided time in which to manage their personal life, they are concerned about the limitation on exposure to patients—yet 96% of these residents would not be willing to add an additional year to their training.¹⁹

There is evidence that about one third of a resident’s time is spent performing activities of marginal or no educational value.²⁰ By eliminating these activities and making better use of simulators and patient surrogates, the workweek could be reduced even further, allowing the physician in training more time for interaction with patients and providing a better balance between work and personal life.

Burnout is widespread

If the goal is to retain physicians in the work-force, it is more important to reduce dissatisfaction than to increase satisfaction. Why? People who are dissatisfied are more likely to change what they are doing than those with any level of satisfaction.⁴

The profession must understand that burnout is common and directly related to increasing dissatisfaction.²¹

Burnout typically occurs when one has a highly demanding position with limited autonomy. A physician experiences burnout when one or more of the following is present:

• emotional exhaustion
• feelings of inadequacy in terms of personal accomplishment
• depersonalization
• increasing cynicism in personal interactions.²¹

This is an accurate description of the current state of medical practice.

Because “the times they are a-changin’,” it is necessary that leaders within the medical profession drastically change the way that medicine is taught and practiced.^22-24

Any further changes—beyond work-hour limitations—should be carefully designed with a mechanism in place to evaluate effects on both physicians and patients. A new approach to the practice of medicine is desperately needed to allow a better work-life balance while maintaining the focus on quality and safety.

Ways to reduce dissatisfaction

Dr. Abigail Zuger summed up the feelings of many when she wrote: “The profession of medicine has taken its members on a wild ride during the past century: a slow, glorious climb in well-being, followed by a steep, stomach-churning fall.”²⁵

I offer the following proposals for discussion. My primary aim in developing these suggestions was to give physicians more of that most precious of commodities: time. More time has the potential to change the work-life balance and improve both professional and personal satisfaction at the same time that it decreases dissatisfaction.

Again: The key to retaining physicians in the workforce is to decrease dissatisfaction. That is more likely to have the desired effect of a larger, stable workforce than is increasing the number of medical students and physicians in training. As is true in most aspects of life, it is easier and cheaper to improve what you already have, recycle what you can, and replace only what is absolutely necessary.

Recommendations—for practitioners, academic and private

• Limit work hours to 50 or fewer per week. Many physicians work too many hours; this is not beneficial to them, their families, and their patients.²⁶ For both patient safety and physician well-being, it is time to voluntarily restrict our work hours before federal legislation creates limits for us.
• Develop new models of practice, such as the use of a laborist for obstetric coverage. The implementation of a hospital-based laborist program allows a safer environment for the patient, a rapid-response team presence, and a controlled lifestyle for physicians who desire to practice obstetrics.²⁷ Structured properly, such models are revenue-neutral for the institution. (See OBG Management’s recent article, “The laborists are here, but can they thrive in US hospitals?” in the August 2008 issue, available at www.obgmanagement.com.)
• Create part-time professional liability insurance policies. Premiums for these policies should be prorated according to the amount of clinical time worked and the physician’s work record. Insurance policies also need to be written to cover a slot rather than a particular individual, so that several physicians can share the same position to equal one full-time practitioner.
• Increase job sharing and part-time employment so that these options become more attractive. With job sharing, two physicians work 50% of the time, adding up to one full-time practitioner. This option will reduce physician dissatisfaction and has the potential to increase the work life of the practitioner while improving patient safety.²⁸ Job sharing will also facilitate recruitment and retention of the current workforce.²⁹
• Acquire time- and money-management skills. Most practitioners need to develop these abilities because so many stressors are related to limits on time and money.
• In academic medicine, revamp the current career trajectory. The timeline that includes tenure and unrealistic expectations for promotion is archaic and needs to be eliminated. Most Generations X and Y physicians find it to be inflexible at exactly the wrong time in their life. Forced to choose between work on one hand and family and personal well-being on the other, they will almost always choose family and personal life first.³⁰ Similar changes are recommended for the private practitioner under consideration for partnership.

Recommendations—for physicians in training

• Limit work hours to 65 or fewer per week. The current 80-hour week is not conducive to improving physician satisfaction or safe care. There is evidence that work exceeding 18 hours a day may impair a physician.³¹ No physician likes working long hours, and it is clearly not safe for patients. Elimination of responsibilities of no or marginal educational value would make a 65-hour work-week practical. Training institutions will need to add more support staff, including physician extenders, to implement a shorter week.
• Increase the use of teaching simulators. This improvement would assist in the development of technical skills. The training institution would be responsible for developing a simulation center. In areas with multiple training programs, a central location would be developed, with cost shared by all parties. Some of the cost would be recouped by the time saved in the operating room. There is also the potential to prevent medical errors and reduce liability cost. (See OBG Management’s recent article, “How simulation can train, and refresh, physicians for critical OB events,” which describes, among other issues, the use of regional simulation centers. The article appeared in the September 2008 issue, available at www.obgmanagement.com.)
• Teach physicians in training time- and money-management skills. Many of the stressors experienced by these young physicians relate to understanding how to budget time and money.
• Sponsor 24-hour, on-site child care at reasonable or no cost. This recommendation for the training institution is important because child care for the dual-career couple is difficult to arrange, often incompatible with the couple’s schedule, and expensive. Any training institution that sponsors a residency program and benefits from this low-cost workforce should be required by the Accreditation Council of Graduate Medical Education to fund this benefit. It is the right thing to do and is certainly a valuable recruiting tool. It will make physicians who have children feel more comfortable working the hours required for their training while removing a major stressor—worrying about their child.
• Supply extra support for residents when a co-resident is on maternity or paternity leave. The training institution should implement this protection to prevent working residents from being penalized when it is necessary for a co-resident to be on leave.
• Create the option of job sharing during residency. In the business world, job sharing has become common and increases satisfaction and productivity. A resident would work half-time, with salary and benefits prorated so that the cost to the sponsoring institution is revenue-neutral. This would be a valuable recruiting tool among residents who are willing to accept a prolonged period of training.

We need a dialogue on these and other recommendations Such a conversation will allow the medical profession to continue to attract and retain the best and brightest professionals. As the satirical poet Auguste Marseille Barthélemy pointed out, way back in 1832: “The absurd man is he who never changes.”