The One Thing I Wish I Knew About Clomid
Clomid is the most popular kid on the block.
Also known as clomiphene citrate, it’s usually the first treatment for infertility and likely the most popular drug on the market. Clomid is a selective estrogen receptor modulator (SERM) meaning it blocks estrogen production. It tricks your body in thinking it’s not making enough estrogen resulting in an increase in production of luteinizing hormone (LH) and follicle stimulating hormone (FSH). Both help stimulate ovulation in women. LH and FSH also help stimulate the production of testosterone and spermatogensis in men.
On paper, it seems like it’s a win-win for both women and men.
I’ve gone through two rounds of IUI. Both required starting Clomid on Day 3. During my first round, I had no idea what to expect. I was crampy and bloated. I felt sluggish and tired. I was traveling out of state for work at the time which meant I needed to bring all of my infertility supplements + time my Clomid in between full day sessions of meetings. You really can’t plan your cyle. It’s never really a “convenient” time to be a Clomid.
My second round of Clomid was awful. Same dosage. Same schedule. My body felt like it was in overdrive. My ultrasound showed larger follicles and more which explained why my level of discomfort was so high. When you’re on Clomid, you cannot wait for that trigger shot. Although Clomid comes with a lot of symptoms, it’s considered the go-to for infertility treatment. As a patient, you implicitly agree to all the meds, all the appointments, all the symptoms that come your way. All the physical and mental baggage is weighed with hopes that something will “just work.”
But here’s the thing with Clomid. Clomid is made up of two isomers:
65% enclomiphene / 38% zuclomiphene
Enclomiphene is an estrogen receptor antagonist meaning it blocks estrogen from binding to estrogen receptors in your brain.
Zuclomiphene is an estrogen receptor agonist which conversely increases estrogen which can accumulate over time.
Zuclomiphene efficacy based on gender-based studies
Men
There are plenty of studies out there on the long-term impact of these isomers on men. Research indicates that zuclomiphene may not play a significant role in Clomid’s outcomes. Another downfall of zuclomiphene is that research suggests that there are long-term side effects. But can enclomiphene work without zuclomiphene? Research suggests yes for men. Then why include zuclomiphene in Clomid in the first place? This points to the need in developing an estrogen receptor antagonist on its own.
Repros Therapeutics tried to do this back in 2015. They developed Androxal, a non-steroidal estrogen receptor antagonist, but it was met with pushback from the FDA. Repros started working on this drug back in 2002 focusing on secondary hypogonadism in men, a pituitary disorder that causes low testosterone. The saga between Repros and the FDA is long. With multiple meetings and reviews of the drug being cancelled, it seems like the FDA wanted out of the conversation. There was too much controversy around the topic at the time. Men started suing other testosterone-drug makers like AbbVie alleging adverse side effects. The FDA tends to be risk averse which likely assumes why they didn’t move forward with Repros.
Women
A 2013 study compared the effects of zuclomiphene compared to clomiphene citrate (Clomid) in women. Although there were no significant comparisons in endometrial development,
“The total number of mature follicles were signicantly more in the enclomiphene group compared to clomiphene citrate group.”
In 2015, the International Journal of Reproduction, Contraception, Obstetrics and Gynecology compared Clomid and Tamoxifen, a selective estrogen receptor modulator (SERM), to determine their efficacy in the induction of ovulation and treatment of polycystic ovarian syndrome (PCOS). Tamoxifen was originally intended as a form of birth control when it was first developed in 1962. Although it proved to be unsuccessful for this purpose, it’s been a fairly successful drug to treat breast cancer in both women and men.
If you take a look at the drug’s listing on the National Library of Medicine website, you’ll find a list of Tamoxifen’s non-FDA approved usages including, you guessed it, “induction of ovulation in the treatment of infertility.”
Bingo.
Like Clomid, Tamoxifen comes with its own side effects including endometrial hyperplasia (an irregular thickening of the uterine lining) and polyp formation. However, Clomid specifically worsens the subendometrial and endometrial vascularization along with the endometrial thickness. This ultimately impacts uterine receptivity. Applied to PCOS patients specifically, ovulatory cycles will be induced but implantation rates will be impacted especially after three rounds of Clomid.
There’s a catch 22 between Clomid and Tamoxifen especially in patients with pre-existing PCOS or endometriosis. The American Journal of Obstetrics & Gynecology reported the exacerbation of endometriosis as a result of premenopausal Tamoxifen exposure.
Conclusion
The infertility community needs to develop an estrogen receptor antagonist (ie: enclomiphene only) for the clinical treatment of infertility among women who choose to go through timed intercourse cycles, IUI, IVF, and mini-IVF.
The medical industry has haphazardly created an alternative to Clomid, but it similarly comes with risks especially to patients with PCOS and endometriosis.
Have a conversation with your reproductive health team about Letrozole. Studies have shown:
Greater effectiveness compared to Clomid for women who are not ovulating on their own. It is typically prescribed after Clomid attemps fail.
Decreased effectiveness for women with unexplained infertlity.
A potential higher incidence of birth defects in pregnancies that used Letrozole to help conceive. As a result, the manufacturer has not filed for FDA approval meaning physicians are still prescribing its use in an “off label” way.
This is such an important conversation to have before you start on your infertility journey. You may end up jointly deciding with your medical team that Clomid is still the right choice for you -
But it's a conversation, not assumption, worth having.
After digging around study after study, there’s a big gap for innovation here. A dedicated team, funding, and additional research is needed to develop an estrogen receptor antagonist to help women on their infertility journey. It may be too late for my “geriatric” generation, but I am hopeful that this initiative will bring promise for the next generation of moms.
Sunny side bump,
Olivia
