Modern medicine often has things backwards when it comes to women’s health. Far from “regulating” hormone levels, hormonal birth control (HBC) deprives the female body of the complementary rise and fall of natural estrogen and progesterone that many bodily systems depend upon for good health. Similarly (and despite its reputation for being the first step towards treating infertility), the way Clomid functions in the body can inhibit certain important aspects of fertility. Let’s dive into how Clomid works, and the side effects or other reasons why using Clomid may not make sense for women struggling with infertility.
What is Clomid and why is it prescribed?
Clomiphene citrate (Clomid, a trademark of Aventisub LLC) is a selective estrogen receptor modulator (SERM) [1]. This means Clomid will bind to some estrogen receptors in the body to send a response (as if the estrogen itself had landed on the receptor), and it will bind to other estrogen receptors to block a response (by blocking estrogen itself from binding to the receptor to send a signal). This creates different effects in different tissues, with the desired result in the ovaries being ovulation. (Notably, SERMs are commonly used in breast cancer treatment because of their ability to block estrogen from feeding estrogen-sensitive tumors.)
How does changing the way estrogen sends signals in the body help with ovulation?
Ovulation starts with the pituitary gland. This small pea-sized gland located within the brain releases follicle stimulating hormone (FSH) to tell the ovaries to start maturing several follicles. This occurs so one (or two) will be ready to release an egg mid-cycle. As those follicles mature and grow, they release estrogen. The ovaries then send a signal to the pituitary gland to let it know that the FSH signal was received and that the ovaries are getting to work. Clomid, however, interferes with this signal, binding to estrogen receptors to prevent the ovaries from responding to the pituitary gland.
Without this response, the pituitary gland will simply try again. It will send out more FSH to make sure the ovaries know to get some follicles ready. This bonus release of FSH causes more follicles to develop than usual, thus increasing the chance that ovulation will occur. This is why Clomid may be given to women who do not regularly ovulate, to help jump start a cycle so an egg can be released and potentially fertilized.
As one might expect, twins are a potential outcome with Clomid treatment. However, a recent study suggests that this rate might be lower than previously thought–around 4%–while previous studies suggested a rate of 10% [2].
Clomid side effects
Ovarian cysts and ovarian cancer
While Clomid is relatively effective at stimulating ovulation, it doesn’t always work. This can lead to the development of large ovarian cysts, so a woman taking Clomid should be evaluated after each round of taking the drug. There is also a small risk of ovarian cancer after prolonged use.
Hot flashes and other perimenopause symptoms
Besides its effects on the ovaries, Clomid and its antiestrogenic effects are responsible for most of the drug’s side effects, including hot flashes, worsening of mental illness, headaches, dizziness, nausea, vision problems, and abnormal bleeding [1].
What’s that about hot flashes? With Clomid, estrogen is not only unable to communicate with the pituitary gland, but with other parts of the brain as well, which impacts how the body regulates temperature. Oddly enough for a drug that’s meant to combat infertility, this effect can create a similar effect as being in perimenopause.
Clomid’s negative effect on estrogen levels and what that does to cervical mucus production
While ovulation is absolutely necessary for conception, it is not sufficient. Other factors impact fertility as well, and unfortunately, these are the factors that Clomid negatively affects. Inhibiting estrogen tricks the body into producing more mature follicles, but it also blocks estrogen from preparing the other reproductive organs for pregnancy.
Ways estrogen prepares the body for a healthy pregnancy
Normally, estrogen signals the endometrium to thicken so a zygote (i.e., an early stage embryo) can successfully implant and receive nourishment. Clomid is known to thin the endometrium, especially at higher doses, which can make implantation less likely [2]. Estrogen also signals the cervix to produce lots of thin, slippery, sperm-friendly cervical mucus, which is necessary for conception because it nourishes and protects the sperm for their long journey up through the fallopian tubes.
But again, Clomid blocks estrogen from sending this signal to the cervix, and even studies from over 30 years ago demonstrate that Clomid decreases the quality of cervical mucus [3].Yes, Clomid may help you ovulate when you otherwise wouldn’t have. But if sperm cannot get past cervical mucus because it’s thick, tacky, or dry, then conception will not occur. If sperm do make it through to fertilize an egg, pregnancy is less likely if the endometrium is not thick enough to support implantation. All together, these side effects could make a patient less likely to conceive and sustain a pregnancy than one who doesn’t take Clomid at all.
Rethinking Clomid
The most common reasons for prescribing Clomid are polycystic ovary syndrome (PCOS) and different types of amenorrhea (including post-pill amenorrhea). But women have alternative treatment options besides Clomid. We encourage those with PCOS who are looking to improve their fertility to read through Natural Womanhood’s bevy of articles on PCOS, including its symptoms, treatment options, and how to manage the condition through nutrition. In a thorough three-part series, we also address the topic of amenorrhea (which is directly related to anovulation), covering the causes of primary amenorrhea, secondary amenorrhea, and treatment possibilities for amenorrhea.
If you do not ovulate or do not ovulate regularly, it may be possible to address the root cause of your condition to restore your fertility. You can reduce excessive stress, make lifestyle modifications, and identify hormone imbalances. Restorative reproductive medicine (RRM)-trained professionals can help to restore ovulation while enhancing whole body health.
Letrozole as an alternative option
Infertility can be a long and difficult journey, and there may be cases where you and your doctor do decide to use medication to help promote ovulation. Letrozole is an aromatase inhibitor and can be used similarly to Clomid to promote ovulation in patients experiencing PCOS [4]. Aromatase is the enzyme that converts androgen into estrogen, and inhibiting this enzyme lowers the overall amount of estrogen in the body. Like Clomid, this causes the pituitary gland to produce more FSH in response, but letrozole does not block estrogen that is present from sending important signals. Furthermore, letrozole is used to treat endometriosis, another common source of infertility.
Controversy
There is some controversy around letrozole as the FDA warns against its use in pregnancy due to toxic effects on the developing embryo/fetus. However, letrozole as a fertility treatment is only used to induce ovulation. It should not be used past ovulation and into pregnancy.
Letrozole vs. Clomid
A 2015 study comparing Clomid and letrozole found that letrozole was associated with higher ovulation and live birth rates in patients with PCOS [5]. A 2014 study found no significant difference in birth defects between babies whose mothers conceived naturally, with Clomid, or with letrozole [6].
Women who get pregnant with letrozole have a lower rate of conceiving multiples. Plus, their babies have lower rates of intrauterine growth restriction. Furthermore, letrozole does not negatively affect endometrial thickness to the same extent as Clomid. This is attributed to the fact that letrozole has a short half-life, meaning that it breaks down faster than Clomid. Because it breaks down faster in the body, it has less time to decrease endometrial thickness [7].
The bottom line
If you’re considering Clomid, or if you are disheartened after trying it and not achieving a pregnancy, know that there are other options out there. It may help to induce ovulation, but it also blocks estrogen’s beneficial effects on cervical mucus production. This Clomid side effect may make conception more difficult to achieve.
Unfortunately, Clomid doesn’t support the whole reproductive system in preparing for conception and pregnancy. Looking for a root cause for anovulation, considering lifestyle changes, learning more about your hormones or potentially considering letrozole as an alternative treatment to Clomid may help improve your fertility and your chances at achieving pregnancy. RRM supports your reproductive system as a whole rather than focusing on a single factor for successful conception.
References:
[1] Mbi Feh MK, Wadhwa R. Clomiphene. [Updated 2022 Jun 27]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK559292/ [2]Takasaki A, Tamura H, Taketani T, Shimamura K, Morioka H, Sugino N. A pilot study to prevent a thin endometrium in patients undergoing clomiphene citrate treatment. J Ovarian Res. 2013 Dec 27;6(1):94. doi: 10.1186/1757-2215-6-94. PMID: 24369731; PMCID: PMC3880974. [3] Marchini, M et al. “Effects of clomiphene citrate on cervical mucus: analysis of some influencing factors.” International journal of fertility vol. 34,2 (1989): 154-9. [4] Peters A, Tadi P. Aromatase Inhibitors. [Updated 2022 Jul 5]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK557856/ [5] Legro RS, Brzyski RG, Diamond MP, Coutifaris C, Schlaff WD, Casson P, Christman GM, Huang H, Yan Q, Alvero R, Haisenleder DJ, Barnhart KT, Bates GW, Usadi R, Lucidi S, Baker V, Trussell JC, Krawetz SA, Snyder P, Ohl D, Santoro N, Eisenberg E, Zhang H; NICHD Reproductive Medicine Network. Letrozole versus clomiphene for infertility in the polycystic ovary syndrome. N Engl J Med. 2014 Jul 10;371(2):119-29. doi: 10.1056/NEJMoa1313517. Erratum in: N Engl J Med. 2014 Oct 9;317(15):1465. PMID: 25006718; PMCID: PMC4175743. [6] Sharma S, Ghosh S, Singh S, Chakravarty A, Ganesh A, Rajani S, Chakravarty BN. Congenital malformations among babies born following letrozole or clomiphene for infertility treatment. PLoS One. 2014 Oct 1;9(10):e108219. doi: 10.1371/journal.pone.0108219. PMID: 25272289; PMCID: PMC4182712. [7] Schram CA. Outdated approach to a common problem. Can Fam Physician. 2016 Sep;62(9):713-6. PMID: 27629665; PMCID: PMC5023340.Additional Reading:
Can birth control cause infertility? Yes…and no
What are the symptoms of PCOS, and how do you treat it?
