Clomid vs. Letrozole

So many people have asked if they should take Clomid or Letrozole and what the difference is. Typically there is a reason why your doctor will choose one or the other, and I know sometimes we forget to explain that reason. However, it is so important for you to know what is going on with your body so you can understand what’s best for you. I see these medications misused often so I want you to understand this topic.

What Are Clomid and Letrozole used for?

These medications are pills that work by trying to amplify the body’s natural signal. First, let’s go over what happens naturally. I like to envision that there is a vault inside your ovaries filled with all of your eggs. When you are born, the vault is full and throughout your life eggs come out of the vault. When the vault is empty, you are in menopause. Every month a group of eggs is released from the vault, and the number of eggs is proportional to how many eggs are still inside. One the eggs will ovulate, and the rest eggs will die. This repeats every month. The eggs are microscopic and grow inside a small fluid filled structure called a follicle. We can see these follicles on ultrasound when checking your antral follicle count. You can also use a blood test to check your AMH (anti-mullerian hormone) that is made from the cells that surround these follicles. These tests measure your ovarian reserve. The brain and the ovary are best friends and they want only one egg to ovulate at a time. At this time, the brain sends out FSH or follicle stimulating hormone, which stimulates a follicle to grow. As the follicle grows, it makes estrogen that causes the lining of the uterine to thicken to prepare for pregnancy. The egg is mature, ovulates, and the follicle forms the corpus luteum. The corpus luteum makes progesterone to support a pregnancy. If you don’t get pregnant, the process starts over again. We use medications like Clomid or Letrozole, which are known as ovulation induction agents, when people are not ovulating and in people who are ovulating, but for a different purpose.

Clomid

Clomid has been around for years and was the first ovulation induction medication in pill form. It stands for clomiphene citrate which is a SERM or selective estrogen receptor modulator. It works by blocking and binding to estrogen receptors so the brain cannot have estrogen bind there. The brain gets worried and says “OMG there’s no estrogen! How do I make estrogen?” Then it sends out a stronger signal of FSH and allows more estrogen to be made from a growing follicle. So when you take Clomid, estrogen receptors are blocked, the body says “hey, there is no estrogen.” You send out a stronger signal of FSH. Sounds simple right? Well not everything is as easy as it seems. The release of FSH is an indirect response so I can’t tell the brain exactly how much to send, and in each person there will be a variable response. Clomid comes in 50mg pills, and people can use 1-4 pills at a time. 200mg is the maximum dosage you would use. Typically it is taken as a pulse for five days giving your body a short term block of the estrogen receptors. However, your body really likes estrogen, and estrogen receptors are found in more than just the brain. This does come with some side effects. When your brain feels like you don’t have estrogen, it can show symptoms similar to menopause like hot flashes, headache, or fatigue. The female brain likes to have estrogen around. You can also have mood changes such as depressive feelings or crying more than usual. Estrogen receptors are also found in the uterus and in five to ten percent of cases a thin uterine lining will be a side effect. This is less than ideal because we want a thick lining to support an ongoing pregnancy. Another side effect can be changes to cervical mucus production. So if you are someone who tracks your cervical mucus, it may not be an effective way to determine when you are ovulating.

When is Clomid used?

Clomid can be used for for people who do not ovulate and can be used for “super ovulation” or controlled ovarian hyper-stimulation in people who do ovulate but have unexplained infertility. It is also used in IVF protocols for someone who is considered a low responder or using a minimal stimulation protocol because it is going to cause a release of natural FSH from the brain. Coincidentally, FSH is the same medication we give in injectable form in IVF to get the eggs to grow. However, it is quite expensive, so this can get the process started with a cheaper and easier way. It’s important to know that Clomid does not help everyone who doesn’t ovulate. For some people, even the highest does not allow them to release enough FSH. If you have hypothalamic amenorrhea, meaning your brain does not have the ability to send out FSH because of caloric restriction, eating disorders, stress, chronic disease, or overexercising. Giving your brain more FSH when it doesn’t have the ability to do so is not going to help. So Clomid is not going to work if you have hypothalamic amenorrhea or hypo hypo.

Letrozole

Clomid and Letrozole are like cousins. They work similarly, but through completely different mechanisms. Letrozole is also known as Femara is am aromatase inhibitor. An aromatase is an enzyme important in the step to make estrogen. An aromatase inhibitor blocks the production of estrogen. The brain senses there is less estrogen but not zero estrogen, which doesn’t give you quite as severe symptoms like Clomid. Because it is not a SERM and you don’t have to worry about the estrogen receptors inside the uterus, you do not see a drop in the uterine lining with Letrozole. Letrozole is a new medication. By newer, I mean 10 plus years. Originally there was a fear that Letrozole could cause in increase in birth defects. Of course that sounds scary, so Letrozole was controversial for a while. However, this has not been seen in very large randomized and controlled trials so we now feel very confident using Letrozole. Similarly, if you are not ovulating because you have Hypo Hypo or FHA and you do not send out FSH, Letrozole is not going to help you. It works by creating a lower estrogen the brain senses and in response sends out an increase in FSH. If your brain can’t do that, it’s not going to work. In this case, you will need injectable gonadotropins or IVF depending on your clinical scenario.

Unexplained Infertility

If you have unexplained infertility, meaning you have periods every month, you are ovulating, have normal fallopian tubes and normal semen anaylsis, please keep reading. Using Clomid or Letrozole empirically or having your doctor hand you a prescription for it and say “try this and have sex,” increses your pregnancy rates zero percent. It is a waste of your time. As a patient, you should tell your doctor that this is not the right treatment for you. Studies of unexplained infertility report the use of medication for super ovulation with an IUI. That will double your chance of getting pregnant and is what you want. In the most up to date study they compared clomid use to letrozole use to gonadotropin use. Letrozole and Clomid both had the highest rates of live birth with the lowest rate of multiples when used for super ovulation. Gonadotrpins had a higher rate of high birth but a significantly higher rate of multiples. With that being said, our goal is to have one healthy baby in your arms and multiples are known to cause more risks.

PCOS

If you have PCOS and do not ovulate, the data has been clear that Letrozle is the preferred medication for live birth rate. Let’s remember that PCOS is when your ovaries have a lot of eggs in them. They don’t respond to the normal FSH signal from the brain. I like to use the analogy that the ovaries start getting a little bored and shift to an androgen production environment causing them to start making more testosterone. This testosterone can cause some of the other symptoms we see such as hair growth, acne, insulin resistance, and central weight gain. You have to break this spell. PCOS is very complicated because there are many different types. I have YouTube Videos and Podcasts on PCOS if you want to learn more. Reminder that sometimes you can do all of the suggestions to manage your PCOS and can still not ovulate. If this is you, please let yourself go of all the self-blame that may exist. Sometimes you may need ovulation induction and that’s okay. It’s why modern medicine exists.

Conclusion

Let’s think about all of this as a whole because this is why there is so much confusion between the two. For some people there are add ons to Clomid or Letrozole for someone who is refractory. Not every medication is going to work for every person. Remember, we are not controlling how much FSH is released. Your brain has to do part of the job. I have some people who will not ovulate on the highest dose of Clomid or Letrozole. I also have people who aren’t responding to one dose, so I up them to the next dose, and they over-respond. If you are going through treatment it’s important to know what you are being treated for, why is this the best option, and what are the goals? Remember that a regular period means that it comes within 1-2 days of each other every month. If you don’t have regular periods, you may fall under the ovulatory disfunction category. Thyroid and prolactin need to be checked. You need to find out if you are running out of eggs. Do you have PCOS or functional hypothalamic amenorrhea? Those are very different and can contribute to failure to ovulate. Treatment may be different for all of these. For unexplained infertility, my patients typically stop at three cycles and move on to IVF. For my anovulatory patients, they typically go up to six cycles. At some point, these patients even may have underlying IVF if they have not gotten pregnant in six months. Before I start any cycle of ovulation induction, I always recommend a full fertility evaluation including semen analysis so we do not waste time. I hope this helped you understand why your doctor may choose Clomid or Letrozole. Please ask your doctor why if you do not know. You deserve the best care possible.