Overview of Ovarian Suppression Therapy

Ovarian suppression therapy is a treatment that may be used for premenopausal breast cancers that are estrogen-receptor positive. It may be used with early-stage breast cancer along with tamoxifen or an aromatase inhibitor to reduce the risk of recurrence, or for metastatic breast cancer to slow the growth of the tumor. Less often, ovarian suppression therapy may be used in an attempt to preserve fertility for women undergoing chemotherapy.

Ovarian suppression therapy can be either permanent (via surgical removal of the ovaries) or temporary (via the use of medications). The most common side effects are related to the temporary or permanent menopause that is created, including hot flashes, mood swings, and vaginal dryness. Long term, potential risks ranging from osteoporosis to heart disease need to be considered.

Recent guidelines are placing greater emphasis on the use of ovarian suppression therapy for women who have a significant risk of recurrence, as the treatment (when combined with tamoxifen or an aromatase inhibitor) is associated with both a lower risk of recurrence and improved survival.

Premenopausal Breast Cancer

Ovarian suppression therapy is used only for premenopausal women with breast cancers that are estrogen-receptor positive. Breast cancer in premenopausal women can be challenging to treat as the ovaries continue to manufacture estrogen, and estrogen, in turn, acts as a fuel for these tumors.

The problem isn't small. Roughly one-third of breast cancers are diagnosed in women under the age of 50. Of these tumors, a 2020 review of studies suggested that around 80% are estrogen-receptor positive.

The challenges with treating premenopausal breast cancer extend both to the potential benefits and potential risks. Premenopausal women, in general, have a poorer prognosis than older women, suggesting that more aggressive therapy should be sought with early-stage tumors.

When these cancers recur, they often do so at distant sites, meaning that the tumor has become stage 4, or metastatic breast cancer. Roughly 90% to 94% of metastatic breast cancers are actually a distant recurrence of a previous early-stage breast cancer.

At stage 4, these cancers are no longer curable, and though there are some long-term survivors, the median survival rate for metastatic breast cancer is only around three years. The risk of recurrence (and hence, the risk of death) in women under the age of 40 is even higher at 1.5 times that of women over age 40.

On the other side of the equation, premenopausal women are not only at a greater risk for long-term side effects of any treatment (because they have much of their life ahead of them), but the common side effects with hormonal treatments are not as well tolerated. The abrupt menopausal symptoms that occur with ovarian suppression therapy differ from the gradual onset of symptoms in women who enter menopause naturally.

You May Be Premenopausal Even If Periods Stop

Many people, even those who are very young, find it confusing to hear they are premenopausal after chemotherapy. Chemotherapy is itself a form of ovarian suppression therapy, and for the majority of women, periods cease during treatment.

Ovarian function is more resilient in younger women, and younger women are more likely to resume menstruating at some point after chemotherapy.

In women over the age of 40, chemotherapy-induced ovarian suppression is more likely to be permanent, and this, in turn, is thought to be linked to improved survival in older women. That said, even if a woman no longer has periods and is near the age of natural menopause, she may still be premenopausal.

The only way to know for certain whether you are pre- or post-menopausal (if you are under the age of 60) is to have a blood test—not just a test for follicle stimulating hormone (FSH), but an extra-sensitive estradiol test.

In addition, even if you are initially postmenopausal after chemotherapy based on a blood test, this can change. Reactivation of ovarian function is of concern especially with aromatase inhibitors, which can stimulate ovarian function, and many healthcare providers recommend monitoring blood tests for menopausal status in those who choose temporary ovarian suppression.

Uses

Ovarian suppression therapy is not a new treatment option. It was, in fact, the first systemic (body-wide) treatment used for women with advanced breast cancer over 100 years ago. Older studies have even found ovarian suppression therapy to be as effective as chemotherapy for estrogen-receptor-positive breast cancer in premenopausal women (but it should not be substituted for this).

With estrogen-receptor-positive breast cancer, estrogen produced by the ovaries acts like a fuel to feed the growth of the cancer. Ovarian suppression therapy uses different methods to essentially shut down the ovaries so they no longer produce estrogen. There are three primary uses for the treatment with cancer.

Reduce Recurrence Risk of Early-Stage Breast Cancer

Ovarian suppression therapy may be used in combination with either tamoxifen or aromatase inhibitors to lower recurrence risk in premenopausal women with estrogen-receptor-positive breast cancers.

The potential benefit of the combination varies depends on a persons age, the stage of their cancer, the tumor grade (aggressiveness of the cancer), lymph node involvement, and more such that some women may benefit substantially, and for others the risks may outweigh the benefits (discussed below).

Ovarian suppression therapy also appears to reduce the risk of developing a second primary breast cancer in the other breast.

With Metastatic Breast Cancer

Ovarian suppression therapy is one component of hormonal therapy that may be used for premenopausal women who have metastatic breast cancer.

To Preserve Fertility

Less commonly, ovarian suppression therapy may be used during chemotherapy, as suppressing the ovaries may offer some protection against the damaging effects of chemotherapy.

Methods

Ovarian suppression therapy may be done surgically or via radiation ablation, which are permanent options, or via medications, which are usually temporary.

Surgical Ovarian Suppression Therapy

The surgical procedure for ovarian suppression therapy is a bilateral salpingo-oophorectomy (BSO). In this procedure, both ovaries and fallopian tubes are removed. While the Fallopian tubes do not secrete estrogen, it's thought that many ovarian cancers begin in the tubes, so they are often removed along with the ovaries.

The surgical procedure can be done in three different ways.

• Laparoscopic BSO: With laparoscopic surgery, most often three small incisions are made in the abdomen and the tubes and ovaries are removed with special instruments. This is usually done as same-day surgery. Laparoscopic surgery is less invasive but is sometimes not possible (for example, if a person has a lot of scar tissue (abdominal adhesions) from previous abdominal surgery).
• Robotic BSO: The robotic procedure is similar to a laparoscopic BSO, but the procedure is done with the assistance of robotics.
• Laparotomy and BSO: With a laparotomy, an incision is made on the lower abdomen (bikini line), and the ovaries are removed manually.

Radiation Ablation

Used less often than surgery or medications, radiation ablation may be used to suppress ovarian function. An advantage is that the procedure is less invasive than surgery, but in some women may result in incomplete suppression of the ovaries. Blood tests are needed to make sure that it continues to be effective.

Medical Ovarian Suppression Therapy

Ovarian suppression can also be accomplished by interfering with the signals from the pituitary/hypothalamus that tell the ovaries to secrete estrogen. Hormones (gonadotropin-stimulating hormones) given once a month by injection lead to less secretion of gonadotropins by the pituitary gland (down-regulation).

This reduced release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) by the pituitary gland decreases signals to the ovaries to produce estrogen and progesterone. Without this stimulation, the ovaries essentially go dormant.

Medications called gonadotropin hormone (GnRH) agonists include:

• Zoladex (goserelin)
• Trelstar, Decapeptyl Depot, or Ipssen (triptorelin)
• Lupron (leuprolide)

GnRH agonists are given by injection either every month or every three months, but when they are discontinued, the ovarian suppression is reversible.

A different GNRH agonist, Firmagon, is also being evaluated in clinical trials. Since conventional GnRH agonists may not maintain suppression in some people (see below), especially when combined with an aromatase inhibitor, other options are being evaluated.

A clinical trial found that, when combined with the aromatase inhibitor letrozol, Firmagon resulted in a more rapid response that was maintained after cycle one. In contrast, triptorelin did not adequately maintain ovarian suppression in 15.4% of people using the injection.

Temporary vs. Permanent Options

The decision to have either surgical/ablation (permanent) or the more temporary medical ovarian suppression therapy is very personal, and there are many issues to consider.

Future desire to have a child: Certainly, if you are hoping to become pregnant in the future, the temporary option would be preferred.

Reversibility: With very young women, oncologists often recommend beginning with medical ovarian suppression therapy since it is reversible. In this way, if side effects are intolerable, the medication can simply be stopped. If the treatment is tolerated well, a surgical procedure can be done at a later date.

Hereditary breast/bvarian cancer: For those who have hereditary breast cancer/ovarian cancer (such as people who carry BRCA mutations or other mutations that raise ovarian cancer risk), the permanent option may be preferable, especially if you do not have a desire to become pregnant in the future.

Studies found that for women who have BRCA mutations and have breast cancer, removal of the ovaries was associated with a 70% lower death rate from all causes and a 60% lower risk of dying from breast cancer (the benefit was seen primarily in people who have BRCA1 mutations (much less so BRCA2 mutations) and if the oophorectomy is done within two years of the breast cancer diagnosis).

A family history of ovarian cancer should also be considered when making a decision even if genetic testing is negative, as current genetic testing is unable to detect all hereditary cancers. Talking with a genetic counselor may be helpful to evaluate your risk.

Side effects and risks: Unlike medications, risks of surgery may include anesthesia complications, bleeding, infection, and others.

Effectiveness: There aren't currently any solid studies comparing the effectiveness of surgery and medication for ovarian suppression in early stage breast cancer, but the two approaches appeared to be similar in people with metastatic breast cancer.

There is some concern, however, especially in women who are overweight, that medical ovarian suppression may be insufficient or inconsistent, and may consequently be less effective. This is of greater concern in women who will also be treated with an aromatase inhibitor (which can, paradoxically, stimulate the ovaries).

In one of the clinical trials showing that ovarian suppression therapy could improve survival in premenopausal women with early-stage breast cancer, a small percentage of the women had suboptimal suppression (based on blood tests), and 16% later underwent either surgery or radiation ablation. For this reason, your healthcare provider may monitor your blood hormone levels with an ultra-sensitive hormone blood test if you choose the medical approach.

Ovarian Suppression to Reduce Recurrence

Looking at ways to reduce the risk of recurrence is critical in women with early stage breast cancer, as roughly 94% of women who have metastatic (stage 4) breast cancer were initially diagnosed with an early stage breast cancer that later recurred. When looking at the risk of recurrence, it is important to look at long-term risk, not just the risk of recurrence in the first five years.

Ovarian suppression therapy has clearly been found to result in improved recurrence-free and overall survival in women less than 50 years of age when diagnosed.

That said, it appears that some premenopausal women with breast cancer are much more likely to benefit from ovarian suppression therapy than others. This is important when weighing the benefits of treatment against the risks and side effects. Several clinical studies (including the SOFT and TEXT trials) have helped narrow down who will benefit the most.

At the current time, ovarian suppression is most often considered in women who have a significant risk of recurrence, such as those with stage II and stage III breast cancers as well as some stage I cancers that are associated with a higher risk of recurrence (people for whom chemotherapy would be recommended) such as a high tumor grade.

When looking at studies to date, it's helpful to compare the use of ovarian suppression therapy with tamoxifen (vs. tamoxifen alone), as well as it's use with tamoxifen vs. an aromatase inhibitor.

Ovarian Suppression Plus Tamoxifen vs. Tamoxifen Alone

When looking at premenopausal women treated with tamoxifen alone versus the combination of tamoxifen plus ovarian suppression therapy, a 2015 study found that combination did not benefit the women as a whole.

That said, among women for whom chemotherapy was recommended and remained premenopausal, the combination provided a significant benefit. This was especially noted among younger women (for example, under the age of 35). A subgroup of people who had tumors that were human epidermal growth factor 2 positive seemed to have the greatest benefit from combination therapy.

In women who had received chemotherapy, adding ovarian suppression therapy to tamoxifen resulted in a 22% lower risk of recurrence, a second breast cancer, or death.

For women under the age of 35, the odds of remaining breast cancer free after five years were 67.7% among women only using tamoxifen, 78.9% in those who received tamoxifen plus ovarian suppression, and 83.4% among women who received an aromatase inhibitor plus ovarian suppression. In this group, one third of the people who received tamoxifen alone experienced a recurrence (55% distant) in 5 years, compared with one-sixth of the combination group (late recurrences after 5 years, however, also need to be considered).

A 2020 study gave further support to these findings, in that combining ovarian suppression therapy to tamoxifen significantly improved both disease-free and overall survival relative to tamoxifen alone.

Ovarian Suppression: Tamoxifen vs. an Aromatase Inhibitor

For women who are premenopausal, tamoxifen must be used rather than an aromatase inhibitor unless ovarian suppression therapy is used. Tamoxifen works by binding to estrogen receptors on breast cancer cells so that estrogen cannot bind (and stimulate growth).

Aromatase inhibitors, in contrast, work by blocking the conversion of androgens in the adrenal glands to estrogen (by an enzyme called an aromatase). Before menopause, the greatest source of estrogen in the body is the ovaries, whereas after menopause, it is from this peripheral conversion of androgens.

Ovarian suppression therapy, by inducing menopause, allows premenopausal women to thus take an aromatase inhibitor. In postmenopausal women, it appears that aromatase inhibitors are 30% more effective in preventing breast cancer recurrence after five years (late recurrence) relative to tamoxifen and decrease the risk of death by 15% after five years.

Studies are suggesting that an aromatase inhibitor may also be preferable to tamoxifen in high-risk premenopausal women. In addition, there are several drug interactions with tamoxifen that may make taking the medication challenging for some women.

Current aromatase inhibitors include:

• Aromasin (exemastane)
• Arimidex (anastrozole)
• Femara (letrozole)

The benefit of combining ovarian suppression therapy with either tamoxifen or an aromatase inhibitor depends on the stage of the tumor as well as a few other characteristics.

In the 2015 study noted earlier, the combination of ovarian suppression therapy and tamoxifen revealed a 28% reduced risk of recurrence, second cancer, or death, and the combination of ovarian suppression and Aromasin showed a 34% reduction.

Lowering the Risk of Late Recurrence

It's worth noting that many studies focus on five-year survival rates with breast cancer. With estrogen-receptor-positive breast cancer, however, recurrences may occur at any time.

In fact, the risk of recurrence remains steady for at least 20 years (among women who receive hormonal therapy for five years after diagnosis). This means that a tumor is as likely to recur 14 years after diagnosis as four years after diagnosis. Early stage estrogen-receptor-positive tumors are actually more likely to recur after five years than in the first five years following diagnosis

Overall, the chance that an estrogen receptor-positive tumor will recur (distant recurrence) between five years and 20 years after diagnosis ranges from 10% to over 41%, and people with these tumors remain at risk for the remainder of their lives.

While chemotherapy is very helpful in reducing recurrence risk in the first five years after diagnosis, it has much less effect on late recurrences. In contrast, hormonal therapy with tamoxifen or an aromatase inhibitor may help reduce late recurrences. This is part of the reason why the length of treatment with these medications is sometimes extended beyond five years.

According to a 2018 study, premenopausal women who have estrogen-receptor-positive, HER2 negative breast cancers, and have a high risk of recurrence may have a 10% to 15% lower risk of distant recurrence at eight years if they receive ovarian suppression therapy.

And, some evidence suggests that the survival benefit of ovarian suppression lasts up to 20 years.

There is a calculator for late recurrence risk that may help people make decisions about hormonal therapy options.

How Often is Ovarian Suppression Therapy Used?

Knowing that ovarian suppression therapy has benefits for some premenopausal women with breast cancer, you may be wondering how often this therapy is used. A 2019 study found that the use of ovarian suppression therapy has been increasing since 2014, and roughly 25% of women overall received ovarian suppression in addition to hormonal therapy.

Among those who received ovarian suppression, more than 30% chose an aromatase inhibitor in combination rather than tamoxifen. This study also found a survival benefit associated with ovarian suppression.

Guidelines on Ovarian Suppression Therapy

The American Society of Clinical Oncology has put forth guidelines for the treatment of premenopausal women with breast cancer. It's important to note that these guidelines are suggestions based on the most recent research, but not absolute rules. There are many nuances when it comes to cancer that general guidelines do not take into account.

In general, premenopausal women who have stage II or stage III breast cancers for which chemotherapy is recommended should receive ovarian suppression therapy. The treatment should also be offered to some women with stage I breast cancer who have a greater risk of recurrence (chemotherapy may also be recommended in this case).

In contrast, women with stage I breast cancers for which chemotherapy is not recommended, or who have tumors that are node-negative and 1 centimeter (cm) or less in diameter should not receive ovarian suppression therapy.

For those who have a high risk of recurrence, for example, women with lymph node positive or larger tumors, the use of an aromatase inhibitor may be considered over tamoxifen because of further reduction in recurrence risk.

Before beginning an aromatase inhibitor, however, women should have an ultra-sensitive estradiol blood test to make sure they are postmenopausal, and this should be repeated periodically unless permanent ovarian suppression via surgery is chosen.

Effectiveness for Metastatic Breast Cancer

When evaluating potential treatments for metastatic breast cancer, it's important to know that the goals of therapy are different than with early stage cancers. With early stage breast cancer, the goal is ultimately a cure (primarily by reducing recurrence risk). Metastatic breast cancer is, at this time, incurable. For this reason, the goal of treatment is to extend survival and improve or maintain quality of life.

For premenopausal women, the effectiveness of ovarian suppression therapy must be weighed against any side effects that lessen quality of life.

An older review of premenopausal women with breast cancer found that combining ovarian suppression therapy (an LHRH agonist) with tamoxifen improved overall survival. Given the advantage of an aromatase inhibitor over tamoxifen in early stage breast cancer, this may be beneficial as well.

Effectiveness in Fertility Preservation

Ovarian suppression therapy with a GnRH agonist may preserve fertility to some degree, but is not a replacement or an alternative for fertility preservation via embryo or egg freezing.

In one study, women who received ovarian suppression therapy were almost twice as likely to become pregnant, but the number remained small (10.3%). It's not known exactly how this works, but may be related to protecting the eggs in the ovary, reducing blood flow to the ovaries, or other mechanisms.

When used for fertility preservation (to try to reduce the chance of premature ovarian failure), ovarian suppression therapy is started at least two to four weeks before chemotherapy begins and continued for the duration of chemotherapy. Women should always be advised to consider embryo or egg preservation at the same time.

Risks and Side Effects

As with any medical treatment, ovarian suppression can have side effects as well as risks. A challenge is that young women with breast cancer (especially very young women) are most likely to benefit from ovarian suppression, but also more likely to be bothered by the side effects of treatment.

Common Side Effects

The most common side effects of ovarian suppression therapy are those due to the temporary or permanent induction of menopause. With surgical or forced menopause these symptoms are usually more dramatic than seen with the gradual onset of natural menopause. Symptoms may include:

• Hot flashes and sweats
• Vaginal dryness
• A decrease in sexual interest/libido
• Mood changes, such as anxiety or depression
• Infertility

When combined with tamoxifen, a review of studies to date found that adding ovarian suppression increased the incidence of severe hot flashes, but did not have a large effect on mood.

Side effects may improve with time. In the SOFT trial, women who received the combination of ovarian suppression therapy and tamoxifen were much more bothered by hot flashes in the first few years of treatment, with no difference from those receiving tamoxifen alone at 60 months.

Loss of sexual interest was very significant at six months, but not present at 24 months or beyond. Sleeping difficulties were present in the first six months but faded after that time. Vaginal dryness was worse in the combined therapy group and continued throughout the study. (In contrast, the group receiving tamoxifen alone experienced more vaginal discharge and itching.)

Compared with the group that used a combination of ovarian suppression and tamoxifen, the group that received ovarian suppression plus an aromatase inhibitor (Arimidex) experienced more sexual problems, bone/muscle pain, and had a greater decrease in their bone density.

In a different trial, significant side effects (grade 3 on a scale of 1 to 4) were present in 31.3% of the group using combination ovarian suppression therapy and tamoxifen and 23.7% of those taking only tamoxifen. These included not flashes, sweating, decreased libido, vaginal dryness, insomnia, depression, musculoskeletal symptoms, high blood pressure, and glucose intolerance (diabetes).

Studies are mixed when it comes to the effect of ovarian suppression on quality of life, with some showing no difference and others showing a reduction.

Serious Side Effects

With medical ovarian suppression therapy, serious effects are primarily related to the induction of menopause. Surgical menopause also carries the general risks of surgery such as bleeding, infection, and anesthesia complications.

It is well known that menopause is associated with osteoporosis, and the incidence in women using combined ovarian suppression therapy plus tamoxifen was 5.8% compared to 3.5% in the tamoxifen alone group.

Aromatase inhibitors, unlike tamoxifen, can lead to osteoporosis as well, and some healthcare providers are recommending using an osteoporosis drug along with therapy. (Since aromatase inhibitors are relatively new compared with tamoxifen, less is known about the long-term effects.)

For post-menopausal women, bisphosphonates are now recommended for some women with early stage breast cancer, not because they lessen the bone loss, but because they are associated with a lower risk of recurrence. These drugs, such as Zometa, work by changing the microenvironment in bone so that bone metastases are less likely to occur (cancer cells that spread to the bones are less likely to "stick."

Researchers have suggested that premenopausal women treated with ovarian suppression therapy plus an aromatase inhibitor may also be good candidates for this treatment.

The risk of other serious side effects is not well known, but early menopause has historically been associated with an increased risk of heart disease and dementia.

Weighing the Risks and Benefits

Before beginning ovarian suppression therapy, it's important to thoroughly educate yourself about the potential benefits and risks. While there are some guidelines in place, these are only suggestions (though backed research). Each woman and each breast cancer is different, and two people with similar types and stages of breast cancer may benefit from or prefer very different approaches.

For those who are concerned about hot flashes, it may be some consolation to note that hot flashes are associated with better breast cancer survival.

A Word From Verywell

It's important to understand the reasons why ovarian suppression therapy may be recommended for your breast cancer, as well as your risk of recurrence. For women with estrogen-receptor-positive tumors (the majority), this includes being aware that late recurrences (10, 20 years after diagnosis) not only happen but are more common than early recurrences (in the first five years).

Knowing your risk, and comparing that with the potential benefit of a treatment won't make your hot flashes go away, but might just make them a little more tolerable and less annoying.