Clomid is the most widely used drug for infertility world wide, accounting for 2/3rds of all drug prescriptions

Clomid
Clomiphene citrate

Take a deep dive with me on the what/how/why of it all using Yen & Jaffe’s textbook as a source.

In the late 50’s, the first non steroidal estrogen antagonist (MER-25) was being tested in patients with estrogen sensitive breast cancer and endometrial hyperplasia

🔑 Many of the endometrial hyperplasia patients had amenorrhea secondary to #PCOS

Clomid
Polycystic ovary

To the investigators surprise, these patients began to cycle regularly with MER-25…cluing them in that they could take advantage of this side effect

🔑 The next generation of estrogen antagonists, clomiphene citrate (MRL/41), proved even better at this.

In 1956 the William S. Merrell Company first synthesized Clomiphene thinking they could use it as a contraceptive

➡️ In 1961 though they published in @JAMA_current
that the medication restored ovulation in 28 of 36 women
➡️ @US_FDA approved it in 1967 for ovulation induction

👀 Interestingly, the William S. Merrell Company were also the makers of thalidomide, and we all now how that turned out….

But we digress!

How clomid work?

Clomiphene is a racemic mixture of 2 stereoisomers
➡️ Enclomiphene has a short half life
➡️ Zuclomiphene has a longer half life

Clomiphene
Clomiphene structure

Together, these isomers block estradiol feedback at the hypothalamus and increase pituitary FSH production by about 50%

🔑 Hence its utility for treatment of anovulatory infertility

How  clomid works
How clomid works

It’s given usually between day 2-5 of a menstrual cycle, no more than 5 days, to allow FSH levels to fall in late follicular phase…to promote mono follicular development.

How clomiphene works
Clomiphene mechanism of action

At doses starting at 50mg/day and increasing to up to 150mg/day with subsequent cycles:

➡️ 60-85% of anovulatory women will become ovulatory
➡️ 30-40% will become pregnant

🔑 50% of women will ovulate at 50mg dose…and another 25% will ovulate at 100mg

It doesn’t work in all women all the time:
➡️ CYP2D6 enzyme polymorphisms may account for some of the variability in response

💩 Fun fact: It is excreted into faeces

Like all good things, there are some side effects:
➡️ hot flushes
➡️ nausea/vomiting
➡️ breast tenderness
➡️ hair loss (reversible)
➡️ blurry vision (reversible)

Also some important pregnancy related side effects
➡️ Risk of multiple pregnancies (<10%) ➡️ OHSS is rare (<2%) ➡️ Long term use may be associated with ovarian cancer (>12 months)

Clomiphene citrate
Clomiphene and multiple gestation

Clomid (clomiphene citrate) is an awesome drug that is effective, affordable, and for many people the only access they have to treatment for infertility

Pietro Bortoletto MD, MSc

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