Sunday, October 30, 2005

How Does Emergency Contraception Work?

How does emergency contraception work? Glad you asked. Let's take a look at the available evidence.

First, some [oversimplified] basics.

What is emergency contraception (EC)?

EC is a group of birth control methods; the postcoital one, to be more exact. When you use a method from another group--an implant, the condom, Persona, sterilization--you use the method before, or during intercourse. When you use an EC method, you use it after you've already had sex. Again, what distinguishes the EC group from the other birth control groups is the timing of use. EC is postcoital (after sex) birth control; all the other methods are used before, or during intercourse:

An emergency contraceptive method is any drug or device used after an unprotected intercourse to prevent an unwanted pregnancy. It is, thus, a method that is used after coitus [sex] but before pregnancy occurs and is, therefore, not an abortifacient.

What are some of the methods in the EC group?

There are two types of EC methods: pills, and intrauterine devices (IUDs). The EC pills (ECPs) can be further subdivided into: high-dose estrogen; estrogen/progesterone (the combination Pill; Yuzpe regimen); progestin-only (Plan B); mifepristone (Mifeprex; RU486); etc. [Our discussion focuses on the pill methods.]:

Trials on emergency contraception were first described in the 1930s using high doses of stilbestrol. In the late 1970s, Yuzpe introduced a regimen consisting of 0.1 mg ethinylestradiol [estrogen] and 0.5 mg levonorgestrel [progestin], given within 72 h of the intercourse and repeated after 12 h.

The "Yuzpe" regimen basically entails using your regular brand of combination birth control pills on a modified, emergency contraception, regimen.

LNG [levonorgestrel] alone [Plan B] has been widely used in contraceptive formulations and has been used successfully for postcoital contraception as well. Higher efficacy and fewer side effects have been recorded when compared to the earlier method using an estrogen-gestagen combination [the "Yuzpe" regimen, or combination Pill]. A large multicenter study comparing the two regimens have shown LNG to prevent about 85% of the expected pregnancies if no other method was used.

Recently, treatment with levonorgestrel-only [Plan B] and mifepristone [Mifeprex, RU486] has emerged as the most effective hormonal methods with very low side effects.

An aside about mifepristone [Mifeprex, RU486]: Its mechanism of action is dose-, and regimen-dependent. When used as a single low dose ECP (older dosage 600 mg; current one, 10 mg), it acts as birth control and prevents pregnancy.

Theoretically, how should EC work to prevent a pregnancy?

Unprotected intercourse may occur at any time during the menstrual cycle but it is only during a limited period, from about 5 days before to 1 day after ovulation* that it may result in a pregnancy. To be effective, postcoital treatment could theoretically target one or several of the following events: sperm transport and function, follicular development [egg maturation, inside the ovary], ovulation, fertilization, embryo development and transport, implantation or the corpus luteum [what's left of the follicle, after the egg has been expelled; essential for early pregnancy support].

*[Recall that sperm may survive in the female reproductive tract for up to five days, and the mature egg may be fertilized over a 24-hour period.]

Second, let's look at what the studies tell us about ECP's mechanism of action.

How does EC work, in real life?

Human and animal studies have shown effects at several stages of the reproductive cycle: ovulation, fertilization, gamete transport, function of the corpus luteum and implantation.

The evidence shows ECPs work by preventing ovulation. There is no direct evidence they prevent fertilization. There's also no direct evidence they prevent implantation in humans.

Looking at ECPs' effect on:

Ovulation (release of mature egg from the ovary)

- inhibit or delay [established, main mechanism of action]

Fertilization (union of egg and sperm)

- no direct evidence for prevention [effect cannot be ruled out]

Gamete Transport

- no evidence of impaired transport in humans

Effects on the Function of the Corpus Luteum

- all pills disrupt this phase, however it is not known whether such changes are incompatible with pregnancy. [Better evidence for mifepristone vs. the other types of ECPs.]

Implantation (burrowing of a fertilized egg into uterus)

- ...although the postovulatory administration of estrogen or levonorgestrel inhibits implantation in some animals, evidence of similar
effects in women has been difficult to obtain. Minor changes in the histologic and biochemical features of the endometrium occur when high-dose estrogen, the estrogen/progestin combination, or danazol is administered after ovulation, but the effects may not be sufficient to inhibit implantation. In a recent morphometric study, postovulatory administration of estrogen plus progestin had only minor effects on the endometrium, and danazol had no effect.

- Mifepristone administered immediately after ovulation delays endometrial maturation

Bottom line:

...the proven mechanisms of action [of the hormones found in ECPs] consist of inhibiting or delaying ovulation.


An emergency contraceptive method is used after coitus but before pregnancy occurs....Recently, treatment with either 10 mg mifepristone [RU486] or 1.5 mg of levonorgestrel [~Plan B] has emerged as the most effective hormonal method for emergency contraception with very low side-effects. However, the knowledge of the mechanism of action of mifepristone and levonorgestrel in humans, when used for contraceptive purposes and especially for emergency contraception, remains incomplete.


When summarized, available data from studies in humans indicate that the contraceptive effects of both levonorgestrel and mifepristone, when used in single low doses for emergency contraception, involve either blockade or delay of ovulation, due to either prevention or delay of the LH surge, rather than to inhibition of implantation.

The last word goes to the NEJM (scroll to the bottom):

Use of emergency contraception is limited largely by ignorance. Although it seems likely that the estrogen/–progestin regimen works mainly by interfering with ovulation, it is nevertheless regarded by many as an abortifacient because it is taken after, rather than before, intercourse. This confusion is compounded when mifepristone is advocated for emergency contraception since, when taken after pregnancy is established, it can be and is used for the induction of abortion. The prevention of pregnancy before implantation is contraception and not abortion. Intervention within 72 hours after intercourse cannot possibly amount to abortion, because implantation is not achieved until at least seven days after ovulation and the egg is capable of being fertilized for only about 24 hours.

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[Pardon the abundance of tags; I've just discovered how to use them.]

Update: More here (via ourword)

Another Update: And make sure not to miss this post on Plan B from Pharyngula.

Wednesday, October 26, 2005

Skipping Your Period: Seasonique

If you are using the combination birth control pill and you want to skip your monthly fake period, when it comes to choosing a brand, you have two options. You can use one of the many Pill brands packaged for birth control [21 days of active pills/7 days of placebo, or hormone-free pills] on a modified regimen [84 days of active pills/7 placebo days]. Or you can use a dedicated brand like Seasonale [84/7].

Either way, once every three months you have one hormone-free week.

Enter Seasonique [I have to ask: who comes up with these puffy product names?], a new brand that completely eliminates the hormone-free interval. Seasonique has 84 active pills (30-μg of estrogen [EE]/150-μg of progestin [levonorgestrel]), followed by 7 more active pills (10-μg EE).

There are two main advantages to replacing the placebo week with a week of low-dose estrogen: a) less, or no bleeding/spotting, and b) fewer, or no symptoms (cramping, bloating, headaches, etc.) for women who are sensitive to the placebo week hormone fluctuations (in particular, low estrogen).

A study* of 1000 sexually active adult women (18-40 years old) who used Seasonique for one year found that for Cycles 2-4, the median number of bleeding days on a per-patient month was minimal (<1.0 days). There were no reports of unexpected adverse events or thromboembolic [blood clot] events. [I haven't seen any data on this brand's effect on the lining of the uterus, so that is one thing to watch out for as more results come in.]

Despite the fufy name, the development of Seasonique is good news. It offers an alternative to women who find the available extended regimen brands less than optimal.

*Portman D, Anderson FD, Gibbons W. Clinical trial to evaluate the safety and efficacy of an extended-regimen oral contraceptive using continuous low-dose ethinyl estradiol. Contraception. September 2005;72(3):230.

Grand Rounds

You can read this week's Grand Rounds (I'm still catching up on last week's edition).


Monday, October 24, 2005

Skipping Your Period: The Patch

Preliminary results* from one of the clinical trials comparing an extended regimen with a cyclic regimen of the birth control patch are in.

One group of women used an extended regimen. The women applied the patch weekly for 12 weeks, followed by one patch-free week. Another group used a cyclic regimen [four consecutive cycles of three weekly patch applications/one patch-free week].

The results:

During the first 56 days of treatment, women receiving the extended regimen versus those receiving the cyclic regimen, respectively, had significantly fewer median bleeding days (1 vs. 9; p<.001), bleeding episodes (0.5 vs. 2; p<.001), bleeding/spotting days (6 vs. 10; p=.009) and bleeding/spotting episodes (1 vs. 2; p<.001) and a higher incidence of amenorrhea [absence of bleeding] (28% vs. 1%; p<.001). Median time to first bleeding with the extended regimen versus the cyclic regimen was 54 versus 25 days, respectively (p<.001).

The conclusion:

Extended-regimen transdermal NGMN/EE [the patch] delays menses and reduces bleeding during the first 56 days of treatment compared with the cyclic regimen, a profile that may be preferred by women who seek flexibility with their contraceptive method.

*LaGuardia KD, Stewart F, Kaunitz AM, et al. Comparison of bleeding/spotting profiles between an extended regimen and a cyclic regimen of transdermal norelgestromin/ethinyl estradiol during the first 56 days of treatment. Contraception. September 2005;72(3):230.

Sunday, October 23, 2005

Vaginal Noises During Sex

Some useful expert advice on the physics of penetration:


What causes vaginal noises with position changes during intercourse? A patient who had a TAHBSO [total-abdominal hysterectomy and bilateral salpingo-oophorectomy (tubes-ovaries removal)] in 2000 and is moderately fit has a small cystocele and rectocele. She is on hormone therapy and has no problem with vaginal dryness. Apparently vaginal noises ("gassy/snuffling sounds") are very loud and have affected her sexual functioning adversely. She came to the office for answers, and I need some help on this one.


The sounds are primarily related to air being forced out of the vagina during thrusting of the penis into the vaginal vault. Air can get trapped in the back of the vagina behind the penis during penetration. As the penis is thrust deeper, the pressure builds and vaginal compliance will reach a peak, causing the air to escape around the penis. The sound created is from the slapping of the vaginal walls (think whoopee cushion).


I have several suggestions for counseling this patient. The first is for the patient to try to modify sexual activity with her partner. If they are able to change positions with the penis still in the vagina, this may decrease air entry during intercourse. Along this same line, any lessening of the degree of removal of the penis and reinsertion will serve to reduce this effect. Additionally, by inserting the penis slowly, the overall volume of the sound will likely be greatly if not completely diminished, as it will allow for a slow leak of the air. Shallower penetration will also help by not creating as great a pressure differential in the air trapped behind the penis.

You may also suggest to the patient that she and her partner try to determine whether there are positions that are more problematic and perhaps not use those positions at the beginning of intercourse or perhaps avoid a particular position if they find the noise too disruptive.

Wednesday, October 12, 2005

Earthquake Aid

Oct. 12 (Bloomberg) -- Pakistan needs more help for relief and recovery after the biggest earthquake in a century in the north, Prime Minister Shaukat Aziz said. Bad weather is hampering aid efforts in the mountainous region struck by the quake.


The official death toll from the 7.6 magnitude earthquake on Oct. 8 is 23,000 and 50,000 injured, Aziz said. That's expected to rise as the army and relief workers reach remote villages and more bodies are pulled from the rubble of flattened cities like Muzaffarabad, the capital of Pakistan-controlled Kashmir, and Balakot, the main centers closest to the earthquake.

If you'd like to help out, feministing has a list of resources.

How To Read Hand Gestures On Your PC

When I tell you that politicians are a menace, perhaps you don't believe me:

BISMARCK, N.D. - To sell things over eBay, Mark Nichols may be required to take instruction in rapid-fire speaking, breathing control and reading hand gestures, even though the transactions are done by computer keyboard and mouse.


Commissioner Kevin Cramer said he does not believe the law applies to people who sell their own goods over eBay, but it could cover those who sell property consigned by others for a fee.

"Our laws probably didn't contemplate this type of commerce," Cramer said. "It's probably time to take a look at them."


Grand Rounds

This week's Grand Rounds is up.


Sunday, October 09, 2005

The Cervical Cancer Vaccine

By now you've already heard the news about Gardasil, Merck's new cervical cancer vaccine targeting the human papillomavirus (HPV):

NEW YORK (Reuters) Oct 06 - An experimental vaccine completely prevented early-stage cervical cancer and precancerous cervical lesions caused by human papillomavirus type 16 and 18, Merck & Co. said on Thursday.

"This trial confirms that a vaccine can give young women a high level of protection from developing precancerous lesions and early cervical cancers," Laura Koutsky, a professor of epidemiology at the University of Washington who led the study, told Reuters.

The favorable findings were seen in a phase III trial sponsored by the U.S. drugmaker, which included more than 12,000 women from 13 countries, aged 16 to 26, who were not infected with either of the virus types when the trial began.

HPV 16 and 18 are responsible for an estimated 70% of cervical cancer cases, and are the targets of Merck's Gardasil vaccine. Such cancers kill about 300,000 women worldwide each year, including almost 4,000 in the United States, Merck said.


Half the women in the trial received three doses of Gardasil over a 6-month period, while the other women received placebo. The women were then followed for an average of 17 months.

Merck said Gardasil was 100% effective in preventing precancerous lesions and early-stage cancers associated with HPV 16 and 18 among women who remained free of infection until they received their final dose of the vaccine. The vaccine thereby easily met its primary trial goal.

By contrast there were 21 cases of lesions and early-stage cancers associated with the two virus types among those taking placebos, Merck said.

Although the vaccine was completely protective against the two virus types, Koutsky said she hopes the vaccine will eventually be improved to protect against up to another half dozen types of the virus that cause cervical cancer.

"In that case, you could be blocking viruses that cause 87% of cervical cancer cases, instead of 70%," she said.

We have already discussed HPV, so let's try to address some of the questions you might have about the vaccine.

Q: Why do we need to vaccinate the population at large?

It's estimated that 75% of the population gets exposed to this very common virus at some point during their lives. Overall:

  • 1% (1.4 million) have genital warts.

  • 4% (5 million) have subclinical disease (evidence of HPV manifestations that are not visible to the naked eye, but could be detected with colposcopic magnification. These subclinical manifestations are most important on the cervix, but may be found anywhere on the lower genital tract. Many of these individuals will have an abnormal Pap smear.)

  • 10% (14 million) are HPV positive (on colposcopy there is no evidence of disease.)

  • 60% (81 million) have been exposed to HPV (A reliable HPV antibody test is likely to be positive, but a direct test for the virus would be negative, indicating that there had been an infection in the past, but the patient developed an immune response and suppressed the virus.)

    So, 75% of the population is exposed to HPV. Once infected, most people's immune system, and/or treatment keep the infection in check. The majority of people with the disease do not progress to cervical cancer. Unfortunately, it is not possible to predict how any one individual will react to being infected with HPV.

    Q: Why are the vaccine trials focused on preferentially vaccinating young women?

    First, why females? By design--because of the cervix--women (young women, as well as pregnant women, regardless of age) are more susceptible. [On the cervix there's an area of transition--from vaginal- to uterine-type tissue. This area is called the transformation zone (TZ); it's an area of high activity. Not only are TZ cells more vulnerable to HPV infection, but, once infected, they're more likely to undergo HPV-induced cancerous transformation. Approximately 90% of cervical cancers occur in this small anatomic region. There is no TZ equivalent on the penis.]

    Click [WARNING! graphic pics] here to see cervical manifestations of HPV in the TZ.

    Second, why young females?

    Because our aim is to prevent infection in the first place.

    In the United States, the average age of menarche [first period] is about 12 years of age. Girls typically initiate intercourse in their mid to late teens. By the age of 20 many would have been exposed to HPV.

    Currently, the way we deal with HPV is to intervene *after* the infection has occurred. However, the ideal approach is to prevent infection in the first place. This could be achieved by the use of a prophylactic HPV vaccine.

    Click here to see a very nice illustration of this concept (Slide 12).

    Q: Why are HPV 16 and 18 the target of Merck's vaccine?

    Because [o]ne of the most important determinants of whether an HPV infection will progress to precancer or cancer is the HPV type.

    Recall that HPV can infect many different sites--the larynx, skin, mouth, esophagus, and the anogenital tract. Over 100 HPV types have been detected; ~20 different types of HPV can infect the anogenital tract. Persistent infection with an oncogenic [cancer-causing] HPV type is the most important risk factor for cervical cancer.

    Infection with high-risk HPV types, most commonly types 16 and 18, cause low-grade cervical cell abnormalities as well as high-grade cervical cell abnormalities that are precursors to invasive cervical cancer. They're also associated with other malignancies including vulvar and anal cancer. [Other high-risk HPV types are 31, 33, and 45.] Infections with low-risk types most commonly types 6 and 11 cause benign or low-grade cervical cell changes and condylomata acuminata otherwise known as genital warts.

    Fast Fact: You have a 60% risk of getting the infection in a single sexual contact with someone who has genital warts.

    So, if you're trying to combat cervical cancer, you need to come up with a vaccine that works against HPV types 16, and 18. If your focus is genital warts you need to develop a vaccine that targets HPV types 6 and 11. [Of course, the ideal solution is to come up with a vaccine that works against all four HPV types--16, 18, 6, and 11. Researchers are working on just such a quadrivalent HPV vaccine.]

    To read a detailed account of the HPV vaccine trials, go here. Of note, the safety of the vaccine:

    When looking at serious adverse effects, we find the numbers in this study are very similar to the numbers in the last study. Notice that for serious adverse effects related to vaccine, the numbers are again zero in both placebo and the vaccine arms, and that during the study 22 patients in the vaccine group and 19 patients in the placebo arm had some sort of adverse reaction.

    Q: Are the researchers working on the HPV vaccine aware of potential barriers to its acceptance?

    Yes they are:

    There are many specific issues that a health care provider may need to deal with when educating patients and their families about HPV vaccination. Foremost are family or parental issues regarding HPV vaccination. The ideal age group for HPV vaccination may well be young teenagers who do not normally have to deal with issues related to sexually transmitted diseases or cancer prevention. Many parents may or may not decide that the vaccine is a good thing for their daughter or feel that their daughter is specifically at risk for the diseases the vaccines prevent. They also may think that it's an issue that can be put off since the child is not sexually active, not understanding the fact that it is best to give the vaccine before initiation of sexual activity.


    There are also specific individual issues that may have to be addressed. There are a lot of health beliefs and lifestyle issues that may be pulled into the debate about whether HPV vaccine is right for specific patients. Specifically, a patient may have issues about perceived susceptibility to the disease process itself, the severity and nature of HPV infection, and the benefits of immunization. We already know from studies that many patients do not know about HPV and are unaware of the serious sequelae that can occur from HPV infection. In fact, less than one-third of men and women in the general population are aware of HPV and its sequelae.

    There may also be cultural issues that have to be dealt with. Some folks may feel that the HPV infection, being an STD, is a deterrent to sexual activity. They may also see the HPV vaccine as condoning or encouraging teenage sexual activity. There also may be distrust of the vaccine itself, or any sort of medical activity or device, and there are specific groups out there who feel like all vaccines are bad.

    Bottom line: The HPV vaccine is an extremely significant development because it offers tremendous possibility in helping reduce the incidence of abnormal Pap smears, cervical cancer, and genital warts in the United States as well as worldwide.

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  • Thursday, October 06, 2005

    Can You Name The Country?

    Q: While there is no ideal contraceptive method mix, it is a concern that in many countries contraceptive use is dominated by one or two methods. However, one country has a method mix that is remarkably balanced in that the 5 leading methods (as of 2004) are quite close, as follows:

    Oral contraceptive -– 15.0%
    Condom - 11.9%
    IUD - 11.5%
    Female Sterilization - 11.5%
    Injection -– 10.4%

    (Overall modern method prevalence is 60.5% and total prevalence is 72.8%)

    Answer (Hint: It is in South America)

    Lasciate Ogne Speranza, Voi Ch'Intrate

    Brilliant news:

    [Chief Justice] Roberts said the federal government has the authority to determine what is a legitimate medical purpose...

    I say the Supreme Court should just rule physicians, nurses, and all healthcare personnel illegal and be done with it. Bonus points if, during the rendering of the decision, all members of Congress gather on the steps of the Capitol and engage in a heartfelt rendition of Kumbaya.

    Grand Rounds

    Don't forget to visit this week's Grand Rounds.


    Saturday, October 01, 2005

    Grand Rounds

    This week's Grand Rounds is the one-year anniversary edition.


    ID and Public Education

    Via Pharyngula:

    This petition is in response to the Discovery Institute's petition "A Scientific Dissent From Darwinism" signed, since 2001, by 400 scientists, as of July 2005. That petition is presented to the public as a scientific endorsement of the religion-based concept of Intelligent Design over Darwinism. Unfortunately, the majority, 83%, of these "scientists" are not schooled in the fields that utilize evolutionary theory in detail, nor even in science, and they are not qualified to present their ideas in a way other than personal opinion. We feel this petition is misleading the public...

    If you're a scientist (biologist, archaeologist, etc.) or educator you might consider signing the petition. [The deadline is 2:09PM EST Saturday Oct 1, 2005.]