Ovarian Function Suppression Therapy in Premenopausal Women with Hormone Receptor-Positive Breast Cancer
Ovarian function suppression (OFS) is a treatment strategy that eliminates estrogen production from the ovaries in premenopausal women with hormone receptor-positive breast cancer, achieved through GnRH agonists (goserelin, leuprolide, triptorelin), surgical oophorectomy, or radiation-induced ovarian ablation. 1, 2
Methods of Achieving Ovarian Suppression
OFS can be accomplished through three distinct approaches, all of which produce comparable clinical outcomes 1:
GnRH agonists (goserelin 3.6 mg every 4 weeks, leuprolide acetate 3.75 mg every 4 weeks, or triptorelin 3.75 mg every 4 weeks) provide reversible ovarian suppression by sustained suppression of follicle-stimulating hormone and luteinizing hormone from the pituitary 1, 3
Surgical oophorectomy provides permanent ovarian suppression and may be preferred by patients who want definitive treatment or wish to avoid ongoing injections 2
Radiation-induced ovarian ablation (typically 20 Gy in 10 fractions) offers permanent suppression as an alternative to surgery 1
The choice between these methods should be guided by patient preference and fertility preservation goals, as GnRH agonists and surgical oophorectomy achieve similar results in both adjuvant and metastatic settings 2.
Clinical Indications for OFS
OFS is NOT routinely recommended for all premenopausal women with hormone receptor-positive breast cancer. The decision hinges on recurrence risk stratification 4:
When OFS Should NOT Be Offered:
- Women with lower-risk, node-negative breast cancer (such as pT2N0M0 triple-positive disease) 4
- Stage I breast cancers not warranting chemotherapy 4
- Node-negative cancers ≤1 cm (T1a, T1b) 4
For these lower-risk patients, tamoxifen monotherapy for 5 years represents optimal management with favorable outcomes and lower toxicity 5.
When OFS Should Be Offered:
- Women with stage II or III breast cancers where adjuvant chemotherapy would ordinarily be advised 4
- Premenopausal women with intermediate to high risk of recurrence 5
- Women with higher-risk features including young age, high-grade tumors, or lymph node involvement 2
Treatment Combinations with OFS
OFS is never used as monotherapy—it must always be combined with endocrine therapy 2:
First-Line Options (All Require OFS):
- OFS + aromatase inhibitor (exemestane, letrozole, or anastrozole) for 5 years—preferred for higher-risk patients 2, 6
- OFS + tamoxifen for 5 years—alternative option 2
The TEXT and SOFT trials demonstrated that exemestane plus OFS significantly reduced recurrence compared to tamoxifen plus OFS (disease-free survival at 5 years: 91.1% vs 87.3%, HR 0.72, P<0.001) 6. However, overall survival did not differ significantly between these regimens 6.
Critical Requirement When Using Aromatase Inhibitors:
Aromatase inhibitors are absolutely contraindicated in premenopausal women without adequate ovarian suppression because the reduction in tissue estrogen can paradoxically lead to increased gonadotropin secretion, causing compensatory rises in ovarian estrogens and possible ovulation 1. This is particularly relevant for women who were premenopausal at diagnosis and are now amenorrheic after chemotherapy 1.
Mandatory Monitoring Requirements
When combining OFS with aromatase inhibitors, rigorous monitoring is essential 2, 7:
Estradiol levels must be measured using high-sensitivity assays to confirm adequate suppression to postmenopausal ranges (<26 pmol/L or <7 pg/mL) 2, 7
Serial assessment of luteinizing hormone, follicle-stimulating hormone, and estradiol is mandatory to ensure true postmenopausal status 2
Monitor before each GnRH agonist dose if under 60 years old and amenorrheic for ≤12 months, after chemotherapy, or when switching from tamoxifen to an aromatase inhibitor 2
Incomplete ovarian suppression can occur, particularly in younger or obese women, and amenorrhea alone does not indicate adequate suppression 7
Vaginal bleeding while on an aromatase inhibitor requires immediate medical attention as it may indicate inadequate ovarian suppression 2
Duration of Treatment
The standard duration of OFS is 5 years when combined with endocrine therapy 1, 2, 4. A minimum of 2 years of OFS is encouraged 2. If no chemotherapy is planned, OFS should be started for at least 1-2 cycles or concurrently with tamoxifen until estradiol reaches the postmenopausal range before switching to an aromatase inhibitor 2.
Important Adverse Effects and Counseling Points
OFS causes substantial adverse effects that must be discussed with patients 4, 8:
Menopausal symptoms: Hot flashes occur in 64% of patients on tamoxifen with OFS versus 48% on placebo 8. Evidence suggests OFS slightly increases the incidence of hot flashes (RR 1.60) 9
Sexual dysfunction: Vaginal dryness, decreased libido, and sexual dysfunction are common 4, 8. In males treated with tamoxifen, loss of libido and impotence have resulted in treatment discontinuation 8
Bone health: OFS increases the risk of osteoporosis (RR 1.16 at median follow-up of 5.6 years) 9
Mood changes: Depression, anxiety, and neuropsychiatric symptoms may occur, though reporting varies across studies 9
Weight gain and cardiovascular effects are additional concerns 4
Fertility Preservation
Fertility preservation must be discussed before initiating OFS, with options including cryopreservation of embryos or oocytes 1, 2, 4. This discussion should include a careful evaluation of the limitations associated with the patient's disease stage and prognosis 1.
Common Pitfalls to Avoid
Never assume amenorrhea indicates adequate ovarian suppression—estradiol levels must be measured, as cessation of menses is not a reliable indicator 7
Do not use 3-month formulations of leuprolide when combined with aromatase inhibitors due to higher risk of incomplete ovarian suppression 7
Maintain ovarian suppression throughout all lines of therapy when switching between hormonal agents (e.g., from aromatase inhibitor to fulvestrant) in the metastatic setting 7
Do not initiate aromatase inhibitors without confirming adequate ovarian suppression through laboratory testing 1, 2