It's an anticancer drug, yet used for fertility treatment? — Why Letrozole is used for PCOS, ovulation induction, and assisted reproductive technology —
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【Table of Contents】
1. Letrozole is not a "drug that directly attacks cancer"
2. Its purpose in breast cancer is to reduce estrogen fuel
3. Its purpose in PCOS and ovulation induction is to grow follicles
4. In assisted reproductive technology, it is used for controlled ovarian stimulation
5. Why does the usage change despite the same mechanism?
6. Points to check when seeing it at the pharmacy
7. Summary
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1. Letrozole is not a "drug that directly attacks cancer"
When you hear the name Letrozole, the first thing that comes to mind is Femara tablets.
It is originally a drug used for postmenopausal breast cancer.
Therefore,
"Why is it used for PCOS or ovulation induction if it's an anticancer drug?"
"Why is it used in assisted reproductive technology?"
you might wonder.
However, Letrozole is not a so-called cytotoxic anticancer drug.
To be precise, it is an aromatase inhibitor.
Aromatase is an enzyme that produces estrogen from androgen.
Letrozole inhibits this enzyme and reduces estrogen production.
In other words, the essence of Letrozole is
"a drug that lowers estrogen"
.
This same action works to reduce growth stimulation of cancer in breast cancer, and is used to promote follicle development in fertility treatment.
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2. Its purpose in breast cancer is to reduce estrogen fuel
Among postmenopausal breast cancers, there is a type that uses estrogen as a growth stimulus.
In estrogen receptor-positive breast cancer, estrogen acts on cancer cells and becomes a signal for proliferation.
After menopause, estrogen production from the ovaries is significantly reduced.
However, in peripheral tissues such as adipose tissue, estrogen is produced from androgen by aromatase.
That is where Letrozole is used.
Letrozole
↓
Aromatase inhibition
↓
Reduced estrogen production
↓
Reduced stimulation to hormone-dependent breast cancer
The purpose in breast cancer treatment is not to directly destroy cancer.
It is to reduce the fuel called estrogen that the cancer is using.
Letrozole → Aromatase inhibition → Reduced estrogen → Reduced growth stimulation to breast cancer cells
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3. Its purpose in PCOS and ovulation induction is to grow follicles
On the other hand, the purpose of using Letrozole in PCOS is ovulation induction.
PCOS stands for Polycystic Ovary Syndrome.
While many small follicles are visible in the ovaries, the follicles do not mature well, and it can be difficult to proceed to ovulation.
In other words, the problem with PCOS is
not the lack of follicles,
but that the process of follicles being selected, growing, and ovulating is disrupted.
Therefore, Letrozole is used for a short period at the beginning of the menstrual cycle.
Letrozole
↓
Aromatase inhibition
↓
Temporary decrease in estrogen
↓
Weakened negative feedback to the hypothalamus and pituitary gland
↓
FSH increases
↓
Follicles grow
↓
Towards ovulation
It is easier to understand Letrozole for PCOS as a drug to induce ovulation for ovulation disorders caused by PCOS, rather than a drug that fundamentally cures PCOS itself.
The approved indication is also
"Ovulation induction in polycystic ovary syndrome"
.
Letrozole → Temporary decrease in estrogen → Increased FSH → Follicle development → Ovulation
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4. In assisted reproductive technology, it is used for controlled ovarian stimulation
Letrozole is not only for ovulation induction in PCOS.
It is also used for controlled ovarian stimulation in assisted reproductive technology.
Assisted reproductive technology is treatment that includes in vitro fertilization and intracytoplasmic sperm injection.
In this field, it is necessary to grow follicles for egg retrieval.
For that purpose, the ovaries are stimulated to control follicle development.
Letrozole promotes FSH secretion by temporarily lowering estrogen, helping follicle development.
Also, depending on the treatment design, it is used in situations where one wants to proceed with follicle development while suppressing excessive estrogen rise.
In other words, Letrozole in assisted reproductive technology is used
not only to induce ovulation,
but as a drug to grow follicles for egg retrieval.
Regarding approval, "controlled ovarian stimulation in assisted reproductive technology" has also been added as an indication.
Assisted reproductive technology → Growing follicles for egg retrieval → Controlled ovarian stimulation with Letrozole
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5. Why does the usage change despite the same mechanism?
In breast cancer, the goal is to keep estrogen low.
In hormone-dependent breast cancer, estrogen becomes fuel for proliferation, so that fuel is reduced.
On the other hand, in fertility treatment, the goal is to temporarily lower estrogen.
When estrogen drops temporarily, the brain judges that "follicle stimulation is insufficient," and FSH secretion is promoted.
Follicle development proceeds due to that FSH.
Even with the same "action of lowering estrogen," the purpose is different.
In breast cancer,
lower estrogen to reduce cancer stimulation.
In PCOS/ovulation induction,
temporarily lower estrogen to release FSH.
In assisted reproductive technology,
regulate follicle development for egg retrieval.
This is the interesting part of Letrozole.
Rather than "it's an anticancer drug, yet used for fertility treatment,"
it is easier to organize if you see it as "it's a drug that moves hormones, so its usage changes depending on the purpose."
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6. Points to check when seeing it at the pharmacy
When you see Letrozole at the pharmacy, you can see the purpose quite well by looking at the dosage and administration.
In postmenopausal breast cancer,
usually, 2.5mg is taken once a day continuously.
On the other hand, in fertility treatment,
usually, 2.5mg is taken once a day for 5 days starting from the 3rd day of the menstrual cycle.
If sufficient effect is not obtained, the dose may be increased to 5mg once a day in subsequent cycles.
In other words,
when you see a prescription for "Letrozole for 5 days,"
you need to consider that it might be for ovulation induction or controlled ovarian stimulation for fertility treatment, not for breast cancer treatment.
The points to check are as follows:
・Is the start date of administration aligned with the menstrual cycle?
・Is it a 5-day administration?
・Is it in the context of PCOS, unexplained infertility, or assisted reproductive technology?
・Has it been confirmed that the patient is not pregnant?
・Is it under the management of a doctor with sufficient knowledge and experience in fertility treatment?
・Have explanations about ovarian hyperstimulation syndrome, multiple pregnancy, etc., been provided?
Letrozole is not a drug to view as "it's strange to use it for fertility treatment because it's an anticancer drug."
It is a drug that utilizes the action of lowering estrogen according to the treatment purpose.
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7. Summary
Letrozole is an aromatase inhibitor.
In breast cancer, it reduces the growth stimulation of hormone-dependent breast cancer by lowering estrogen.
In ovulation induction for PCOS or unexplained infertility, it promotes FSH secretion and helps follicle development and ovulation by temporarily lowering estrogen.
In assisted reproductive technology, it is used as controlled ovarian stimulation for egg retrieval.
Even with the same action, the purpose of use is different.
In postmenopausal breast cancer, it is a drug to reduce cancer fuel.
In PCOS/ovulation induction, it is a drug to turn on the switch for ovulation.
In assisted reproductive technology, it is a drug to regulate follicle development.
Rather than "anticancer drug, yet fertility treatment,"
"because it is a drug that lowers estrogen, it can be applied to breast cancer, ovulation induction, and assisted reproductive technology"
this is the clinical perspective on Letrozole.
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References
・PMDA Femara Tablets 2.5mg Review Report
https://www.pmda.go.jp/drugs/2022/P20220913001/300242000_21800AMY10006_A100_1.pdf
・PMDA Review Report and Preliminary Evaluation Report for Publicly Known Application Items
https://www.pmda.go.jp/review-services/drug-reviews/review-information/p-drugs/0038.html
・Ministry of Health, Labour and Welfare, Review Committee on Unapproved Drugs and Drugs with High Medical Needs
Report on the Applicability of Letrozole for Ovulation Induction in Polycystic Ovary Syndrome to Publicly Known Application
https://www.mhlw.go.jp/content/11120000/000891512.pdf
・Letrozole Tablets Package Insert
https://www.pmda.go.jp/PmdaSearch/iyakuSearch/