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What is the most effective fertility drug?

What is the most effective fertility drug?

Nicole Knight, AHCJ | June 15, 2021 | Getting Pregnant
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If you’ve been scouring the internet for information on the best fertility drugs, you’ve probably seen names like clomiphene citrate and letrozole in your search results. Both are commonly used in fertility treatment. But you may wonder...which fertility drug is most effective?

To answer this question and others, we enlisted the expertise of Dr. Clarisa Gracia, Chief of Reproductive Endocrinology and Fertility at the University of Pennsylvania. 

Our interview with Dr. Gracia covers the most pressing questions that we hear about fertility drugs. Read on for accurate, evidence-based answers on fertility medications, age-related infertility, luteal phase defect, and more. 

When do you advise women to start taking a fertility drug?

Generally, we advise women to seek an evaluation, figure out what's happening, and then pursue a treatment that will address the particular problem. 

Typically, we define infertility as a year of unprotected intercourse without conceiving, and we start the evaluation at that time in women under age 35. For women over age 35 — because age is an issue for women, and as they get older, it becomes more difficult to become pregnant — we start the evaluation at about 6 months.

The evaluation typically involves an assessment of the uterus and Fallopian tubes to see if they're open, an evaluation of sperm quality, and also we look to see if a woman is having regular menstrual cycles and ovulating every month. Then once we have all of that information, we can figure out the best strategy for treating her.

I know that this follow up question varies based on the infertility diagnosis, but what is the most common fertility drug? 

Probably the most common fertility drug that's prescribed in the United States is clomiphene citrate (Clomid®). This is a pill a woman takes 5 days out of the month, typically between days 4 and 5 of the menstrual cycle, for 5 days. Clomiphene citrate is an estrogen antagonist, which essentially causes the pituitary gland to secrete more follicle-stimulating hormone, which is the hormone that stimulates the growth of eggs in the ovaries. For a woman who's not ovulating regularly, Clomid can help induce ovulation. For women ovulating every month, it can increase the number of eggs released per cycle — so kind of upping the odds of pregnancy happening.

I imagine if it's increasing the number of eggs, then there's an increased chance of multiples? 

One of the side effects is an increased risk of multiples. However, with medications like clomiphene citrate, generally 90% of the babies born are singles. There's only a 10% chance of multiples, and it's pretty rare to have anything more than twins.

The media can make it seem like having more than multiples is common, but it is reassuring to hear that it is rare.  Who is the best candidate to take clomiphene citrate?

The best patients are women who are either not ovulating regularly, women who typically don't get periods every month, or women who are ovulating and have what we call unexplained infertility. Unexplained infertility means their tubes are open, there's good quality sperm, but we can't figure out a reason for the fertility problem — and simply increasing the number of eggs released per month can increase their odds of pregnancy. 

Often, in such patients, we combine Clomid with intrauterine insemination (IUI). IUI is where we take the sperm, we concentrate it, and put it into the uterus when a woman is ovulating. So not only do we have more eggs, but we also have more sperm in the right place at the right time, which increases the odds of pregnancy.

So that would lead to our next question, which is how successful is it, on average?

In a couple with a woman who's under age 40, the combination of clomiphene citrate plus IUI typically has a success rate of about 8% per month. It sounds very low, but in a couple that has been trying to get pregnant for at least a year, the odds of them getting pregnant on their own are often as low as 2-3%. 

Clomid alone doesn't work quite as well, and may increase the odds slightly, to 4-6% in that population. But success really depends on your age and exactly what's happening with your fertility diagnosis.

Thanks for sharing the statistics. Those aren’t easy to find online, and I’m sure they are helpful for managing expectations. Sounds like a powerful drug. What are the side effects? Are there any that women should be worried about?

Some of the side effects of clomiphene citrate include hot flashes, night sweats, bloating, and some people get mood changes. You might have a little bit more discomfort with ovulation because you have more than one egg in your ovaries, and your ovaries may get a little larger. Generally, they're pretty mild symptoms and well-tolerated.

What about with a combination of treatments? Are there any additional risks?

Theoretically, you could have an infection from insemination, but it's very very rare. Personally, I've never seen an infection from insemination; it's extremely rare. 

Generally, it's the medication that causes the side effects, and the biggest issue, which you did bring up, is the risk of multiple pregnancies. Ideally, a woman gets pregnant with one baby at a time because twins do pose a higher risk to the woman and the babies. 

For women who Clomid is not working for, or who are afraid of the side effects, what alternatives are there, if any?

Medications that are similar to Clomid include a drug called letrozole, which is an aromatase inhibitor. It basically makes your body produce less estrogen and causes a higher production of follicle-stimulating hormone (FSH), which then increases the odds of ovulation. 

Letrozole can be used to increase the number of eggs per month. It's very commonly used, and it seems to work a little better in women who don't ovulate regularly, like women with polycystic ovary syndrome (PCOS). So we tend to use letrozole in those women more than clomiphene citrate, I would say.  

Other medications include FSH itself. Typically it has to be injected. FSH directly influences the ovary to produce more eggs, but it has a higher risk of multiple pregnancies, actually closer to 25% in combination with insemination. We use FSH much less because it is a little bit riskier. 

Letrozole is mostly used for women who are doing in vitro fertilization (IVF). In IVF, we're stimulating anywhere from potentially 5-30 eggs within a menstrual cycle, and then we're going in and retrieving the eggs using a minor surgical procedure, fertilizing the eggs in the laboratory, and then transferring an embryo into the uterus. So, for women who want to avoid multiple pregnancies, we can select a single embryo to transfer, reducing the risk of multiple pregnancies.

It must not be an easy decision, what to start with or if to go straight to IVF. Especially since they're having to balance the risk of having to do it again, right?

Right. I mean, IVF is the most successful treatment we have, so it definitely works the best. But it is a lot for a woman to go through. It's expensive, many insurance plans don't cover it, so it is a challenge for couples to make these decisions.

Do you guide couples in making that decision? I imagine it's based on age and their infertility diagnosis. What would you say is the first step? Is that too dependent on the individual, or is there a first step before IVF?

The first step is doing the workup and figuring out the cause of infertility. If the sperm count is extremely low or the tubes are blocked, we may go straight IVF.  Because no matter how much medication you administer, if your tubes are blocked, or you don't have enough sperm, it's not going to work.

In other cases, where we do have open tubes and good quality sperm, we start with medications like Clomid or letrozole, typically around 6 cycles of Clomid with intrauterine insemination. Then if that doesn't work, we move to IVF.

Now when the women are 38 or older, there's some evidence that suggests IVF works better and faster for those women. In those patients, we often talk about doing IVF as a first step. But again, sometimes there are restrictions, depending on what a patient wants to do or what insurance might cover. So those are things to think about.

At what age would you stop recommending fertility treatment? You know we're waiting so much longer to start having children, and 38 feels like the new 28 to many women. 

That's very, very true. There are lots of women who are waiting, you know, and it takes a while to meet the man of your dreams, and sometimes people never do meet the man of their dreams. I think that women want to pursue their careers, and there are lots of opportunities for women. Some women are seeing us about freezing their eggs, and talking about these options, and it's always a good idea to be proactive about your fertility.

The problem is that fertility does decline as a woman gets older. It goes down after 35, down even more after 40, and by 45, it's extremely rare for a woman to get pregnant on her own, even with fertility treatments, IVF, etc. It just does not work well, generally over age 42, the success of fertility treatment is very low at that age and later.

What can work for older women is to use an egg from another woman, a younger woman, with your partner's sperm and to carry the pregnancy. But obviously, most individuals want to have a genetic child if they can.

Many of us are aware that age is the most common cause of infertility but what health conditions can cause  infertility?

I would say it depends on the population overall. In about 40-50% of cases, there's some sort of a male factor, such as low sperm quality. Depending on the population, about 20-30% of women may have a tubal issue. 

Many patients I see have unexplained infertility or age-related infertility. Age-related is the biggest population we're seeing now. As women delay childbearing, it becomes harder to get pregnant. 

It's a good idea to seek treatment and evaluation sooner because of that, especially if you're thinking about your second or third child, and you're starting the process at, say, age 39.

Secondary infertility, I think, doesn't get as much attention as primary infertility, but if I heard you correctly, it's common?

It's common because of the age factor more than anything else. For example, maybe you had your first child in your late 30s, but now you're in your 40s, and the quality of your eggs has gone down. 

We hear about PCOS a lot at Kindara. As a reason for fertility issues, would you think that PCOS comes after age-related infertility?

About one-third of patients experience ovulatory problems like PCOS. We see PCOS quite a bit. 

Typically PCOS is characterized by irregular menstrual cycles. Usually, the menstrual cycles are spaced apart, generally at least 45 days from the onset of one period to the onset of the next period. 

With PCOS, there can be high levels of male hormone. The ovaries also have a very specific appearance where they have lots and lots of eggs or follicles. Women with PCOS have more eggs than usual, and there seems to be a problem with those eggs getting released in a regular way. So then, if you don't ovulate, it's more challenging to get pregnant on your own and to time intercourse.

Makes sense if you are not ovulating that it is more difficult to get pregnant, but I don’t think it is common knowledge that women with PCOS actually have more eggs than usual!  Do the same drugs work for PCOS as with age-related infertility?

For women with PCOS, we typically would do an evaluation with hormone testing to make sure PCOS is what they have. Irregular periods could mean other things, like thyroid problems, or could be a sign of premature ovarian insufficiency, which means you're running out of eggs early. It is important to get tested to see what is going on. 

After a PCOS diagnosis, you typically start with medications after ruling out sperm issues. Letrozole would be my first-line recommendation. I'd then monitor ovulation through ultrasound to see if a follicle or egg is being produced, and then help patients to time intercourse.

My last question is concerning cycle length and progesterone. We hear from women often, either by them sharing their story with us or on social media that they didn’t have enough progesterone to carry a pregnancy.  But it is known that luteal phase defect is up for debate for being a real thing or not. Do you have any thoughts on that?

I think there's been a lot of controversy about luteal phase defect. It refers to when a follicle is ovulated, but there's insufficient progesterone to support a pregnancy. 

Certainly, as women age, there's good evidence that progesterone levels go down, and that might contribute to some of the problems getting pregnant as women get older. 

I think there probably is something to it. I think it's very difficult to diagnose, other than with a short luteal phase (from the time you ovulate to the time you get to your next period). Short is less than 10 days — that's a sign sometimes. 

With a luteal phase defect, you can use medications like Clomid. Because when you increase the number of eggs released, that can release more progesterone, and address a luteal phase defect. Or you can try progesterone supplementation. But a luteal phase defect is hard to actually diagnose. 

That is all I’ve got for today, but I'm curious whether there is a commonly asked question by your patients that we haven't covered here?

I think we hit most of the questions and gave a good overview. I would encourage patients with concerns about their fertility to talk to their gynecologist or a fertility specialist. I think it can be helpful to have a better understanding of what's going on with your body, and then move forward with treatment, if it's indicated. 

Have more questions on why you haven’t gotten pregnant yet? Read Kindara’s two-part series on infertility.

Interview:  Dr. Clarisa Gracia, Chief of Reproductive Endocrinology and Fertility at the University of Pennsylvania. 

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