Premature Menopause: The Unexpected Symptoms of Cancer Treatment

When most younger women think of menopause, they think of their mothers having hot flashes at the dinner table or hearing about sleepless nights from their aunts but women dealing with cancer at many ages may experience these symptoms. Menopause can manifest in a variety of ways including hot flashes, mood swings, changes in sex drive, and memory loss. While the average age of menopause in the United States is 51, cancer treatments can induce premature menopause, either permanently or temporarily, in much younger women. Survivors of childhood cancer are also up to 13 times more likely to experience premature menopause than women without a cancer history.

The menopausal change is an important issue at any time in a woman’s life but women who are simultaneously dealing with a cancer diagnosis and treatment are even less prepared than older women. In ageing women, menopause is caused by a gradual shutting-down of the ovaries at the end of the reproductive years. With “the change,” the ovaries stop producing the hormones estrogen and progesterone. This hormonal withdrawal causes many of the symptoms of menopause. Young women undergoing a variety of cancer treatments may experience a sudden onset of menopause and its symptoms.

Chemotherapies that cause damage to the ovaries (and cause permanent or temporary infertility) can cause menopause. Some chemotherapies, such as those with alkylating agents, are more likely than others to increase the risk of infertility and menopause. In addition, radiation therapy to the pelvic areas or the brain can induce menopause by damaging the ovaries directly or disrupting the parts of the brain that control ovarian function. Women with ovarian cancer and some cases of breast cancer may have their ovaries surgically removed, which pushes them into a premature menopause termed “surgical menopause.” Some chemical methods of cancer prevention, such as tamoxifen, are prescribed to young women to reduce the risk for primary breast cancer or relapse. Tamoxifen works by interfering with estrogen signaling in the body that can increase the proliferation of cancerous cells but can also commonly cause menopausal side effects in women, though it does not cause menopause.

As with older women, symptoms for premature menopause due to cancer therapy may vary greatly between women. Cancer survivors with premature menopause experience a longer percentage of their lives without the natural protective effects of estrogens. These hormones are important for maintaining bone and heart health and cancer survivors may be at increased risks of long-term effects of premature menopause such as osteoporosis and cardiovascular disease. A new documentary, called Hot Flash Havoc, aims to explain some of these risks and includes interviews with women who experienced premature menopause in their 30s. The Institute for Women’s Health Research is hosting an event with a panel of experts and pre-screening of the documentary on Wednesday, February 2nd in Chicago, IL.

New Publication: Oncofertility and Gender Roles

Investigators at the Oncofertility Consortium recently published a discussion on historical perceptions of infertility in the Journal of Cancer Survivorship. The authors, Shauna Gardino, Sarah Rodriguez, PhD, and Lisa Campo-Engelstein, PhD, related this evidence to contemporary responses to real or perceived fertility loss by male and female cancer survivors. Since oncofertility is a new field, studying infertility and gender allows researchers to gain an understanding of the desire for fertility preservation in male and female cancer patients.

In “Infertility, Cancer, and Changing Gender Norms,” the authors identify that men and women may differently value their reproductive potentials and delve into historical views of infertility between genders. Infertility has often been considered a female problem-though both genders are equally likely to experience infertility. With the advent of modern-day medicine, infertility became a treatable condition for both men and women but, until recent times, almost all patients seeking infertility treatments were women.  The authors further explore the psychological reactions that men and women experience when receiving a diagnosis of infertility and how that has changed over time.

Recent studies have examined the value cancer survivors place on their fertility and it they are distressed by its potential loss. Interestingly, early research identified such values primarily in women but current literature increasingly finds fertility concerns in men, indicating that gender differences in infertility concerns may be decreasing. Perceptions of fertility, infertility, and parenthood have changed rapidly over the past few decades. In the United States, men are more active in child rearing than a generation ago and the authors stipulate that this may play a role on the changing values that men and women place on having biological children.

The National Institutes of Health, which funds the research of the Oncofertility Consortium, supports investigating the changing perception of fertility by cancer survivors, as it can guide fertility preservation recommendations to patients. This new information can help health care providers better care for cancer patients as they make fertility preservation decisions in the short time between diagnosis and treatment.

To learn more information about the history of fertility, join us online at the February 10th Oncofertility Consortium Virtual Grand Rounds with Margaret Marsh, PhD, and Wanda Ronner, MD, who will discuss “The Fertility Doctor: John Rock and the Reproductive Revolution.”

ASCO University for Cancer Providers

The American Society for Clinical Oncology provides continuing education for medical professionals on a range of topics. One recently-launched module, Focus Under Forty, disseminates information to help providers best care for patients between 15 and 39 years old. The free presentations identify the unique challenges that young cancer patients and survivors face in the realm of supportive and cancer care.

The seminars identify medical risks that cancer disease or its treatment may cause for young patients. Some issues, such as osteoporosis and blood clots, may affect adolescents and young adults more than children. Other problems identified in the module are caused by specific cancer therapies, such as anthracycline and high doses of cyclophosphamide, which can increase the risk of heart problems. These and other therapies may also impair the future fertility of cancer survivors. The module further discusses how women who are already pregnant when diagnosed with cancer face their own unique dilemmas, as many therapies may affect the development of a fetus.

The ASCO modules also provide sample questions for health care providers to ask young patients about various aspects of their health. In addition, it provides resources for clinicians and patients to support their needs. This information provides the framework for medical professionals to increase their understanding about cancer in young people and better care for them. Clinicians with detailed questions about fertility and cancer treatment can also call the Oncofertility Consortium‘s FERTline hotline at 866/708-FERT (3378).

National Cancer Institute Committed to Oncofertility

In 1971, the National Cancer Act was signed in to law to find a cure for cancer through research and clinical trials. Since that time, scientists have learned many nuances about cancerous cells and tissues and significantly increased survivorship rates for many cancers. Where a cancer diagnosis used to be a death warrant, today it can be a manageable disease.

As survival rates increase, the National Cancer Institute (NCI), which coordinates federal funding of research, training, and education about cancer, has increased their efforts in survivorship issues, such as secondary cancers and infertility. To support this mission, the NCI included the Oncofertility Consortium in a national list of organizations that provides services to cancer patients and caregivers.

In addition to providing information to patients, the NCI communicates to the larger broader cancer community through its biweekly online NCI Cancer Bulletin. The current version of the newsletter is the NCI’s 250th and includes the article, “Preserving Fertility While Battling Cancer.” The piece discusses the gap between clinical guidelines and fertility preservation care for patients. Fortunately, researchers around the country are developing new fertility preservation treatments and developing tools that will help young patients make significant decisions about their future in the short period of time between diagnosis and treatment. The article highlights some of these researchers, including the Oncofertility Consortium‘s director, Dr. Teresa Woodruff. Continued support from the NCI will someday allow all young cancer patients to spare their fertility and, simultaneously, receive life-saving cancer treatments.

Obesity, Oncology, and Oncofertility

A recent seminar about the role of obesity on breast cancer got me thinking about how weight affects all types of cancer. In the United States, where a third of people are obese, many patients experience weight-related complications in cancer diagnosis and treatment. Obesity increases the risk and mortality rates for colon, breast, endometrial, kidney, esophageal, and other cancers. As unhealthy weights are increasing throughout most of the world, it is important to understand the relationship weight plays on cancer occurrence, treatment, and oncofertility.

In some cases, the link between cancer and obesity is well understood. Adipose tissue, or fat, produces the hormone estrogen that can increase the proliferation of some cancer cells. Hormone-responsive breast tumors are especially sensitive to estrogen, causing obese women to have a 50% increased risk for breast cancer than healthy weight women. Weight loss is negatively correlated with breast cancers, which gives women an opportunity to immediately reduce their cancer risk. Persistently high insulin levels caused by weight gain may also increase the risk for some cancers, including colorectal cancer.

Other cancers are correlated with increased cancer risk but have unknown etiology. For example, a type of esophageal cancer, called adenocarcinoma, and some stomach cancers are linked to obesity, possibly through gastric reflux disease, but no biological mechanism has further explained this link.

In addition to increasing the prospect of developing cancer, obesity can reduce the ability to diagnose abnormally dividing cells. This is because a variety of cancers, including those of the prostate and breast, are less likely to be detected in obese men and women. Obesity is correlated with reduced survivorship in these types of cancers.

Once diagnosed, obesity may continue to impact treatment success. Many chemotherapy does are calculated by body surface area rather than weight, which may lead obese people to receive ineffective doses of chemotherapy. One study also suggests that cancerous cells might not receive full doses of radiation in obese people.

Survivors can benefit from weight loss even after beating cancer. Multiple studies describe an improved quality-of-life in cancer survivors of healthy rather than obese weights. As we all know, fertility is one of the most important issues to young cancer survivors, who already have reduced chances for achieving a spontaneous pregnancy. By itself, obesity can reduce testosterone levels in men and cause ovulation and other conception problems for women, thus inhibiting fertility. Fortunately, survivors can be proactive in this oncofertility issue by developing healthy eating and exercise habits to pass on to the next generation.

Testing Female Fertility After Cancer

Our recent blog on the reproductive options for cancer survivors who do not receive fertility preservation raised some interesting questions. As mentioned in the post, while there is no definitive way to determine if anyone is fertile prior to attempting to conceive, some medical testing can give a good indication of future reproductive potential. Dr. Jennifer Hirshfeld-Cytron, recently discussed these tests with us and said, “what a woman does if she had cancer is the same as if she is over age 40,” and wants to learn about her fertility. A variety of hormonal tests are available that may give such clues for women, often as indicators of the ovarian reserve, the potential of an ovary to produce eggs capable of fertilization.

Two hormone tests, for follicle-stimulating hormone (FSH) and estrogen, are often initially performed to determine reproductive potential in women. FSH is a hormone that stimulates the growth of follicles in the ovary and, when measured the third day after a woman begins her menstrual flow, can indicate potential fertility. Most fertile women have FSH levels below 10 mIU/ml at Day 3, although exact clinical determinations can vary. Menopausal women and cancer survivors who have lost reproductive ability may have elevated FSH levels at this time. Estradiol, the primary type of estrogen in women, is also low at Day 3 in most fertile women.

Another important hormone, inhibin B, can be measured to indicate fertility. Inhibin B is produced by antral follicles, small follicles that require FSH to survive. Interestingly, as small antral follicles grow, they produce inhibin B, which then inhibits FSH production. Three days after menstruation begins, inhibin B is normally elevated but these tests are harder to interpret and, therefore, used less regularly than FSH and estrogen.

The two gold-standard measurements for ovarian reserve test anti-Müllerian hormone (AMH) levels and a woman’s antral follicle count. While AMH testing has been in existence for years, research resulted in its increased utility during recent years. AMH is a less variable hormone that  increases during puberty and remains constant until menopause. Granulosa cells, specialized “nurse cells” within follicles, produce AMH that also remains relatively stable across the menstrual cycle. Thus, this test can be used at any point in the menstrual cycle and even when a woman is taking hormonal birth control.

An additional reproductive test for cancer survivors interested in preserving their fertility is a count of their antral follicles at the beginning of the menstrual cycle. These follicles can be viewed near the surface of the ovary with an ultrasound. It is important to note that these counts are good indicators of the number of eggs that may be retrieved through hormonal stimulation during in vitro fertilization procedures, rather than the spontaneous pregnancies that may be an option for cancer survivors.

Future research will determine if these tests can be tailored to cancer survivors. One effect of cancer treatment can be temporary or permanent infertility begining during therapy that continues for months, years, or forever. Clarisa Gracia MD, an Oncofertility Consortium investigator, examines how fertility measurements change during and after active cancer treatment. Potentially, such measurements could provide personalized treatment to women that would destroy their cancers and, simultaneously, allow them to retain reproductive ability.

Fertility Options AFTER Cancer

We at the Oncofertility Consortium spend much of our time developing new techniques and options for young cancer patients who wish to preserve their fertility before undergoing cancer therapy. But what options are available to cancer survivors who did not undergo fertility-sparing treatments?

Cancer patients may not protect their reproductive potential before beginning cancer treatment for many reasons including an immediate need for care, unavailable options near a patient’s home, and young age at cancer diagnosis, among others. Once they successfully beat cancer and start thinking about the future, young people may begin to wonder about their reproductive options. Since tailored treatments are used to combat each distinct case of cancer, fertility is also differently affected in every case. Treatments that may affect fertility include surgery, radiation, and chemotherapy. Even the doses, locations, and combinations of these treatments may affect later reproductive ability. Finally, these variables can alter the fertility of individual cancer fighters in different ways.

Survivors who wonder about the impact of cancer treatment on their reproductive potential should talk with a physician or fertility counselor. Survivors with additional questions or need for referrals can contact the FERTline oncofertility patient navigators. Analysis of a man’s semen sample can determine if the number and mobility of sperm indicates diminished fertility. Women may have their ovaries, fallopian tubes, and uterus examined and their hormone levels measured. Though these tests may give an indication of fertility, there is no sure-fire way to determine person’s reproductive potential until he or she attempts to conceive a child.

Cancer survivors who find their fertility impaired may use one of the many options in assisted reproductive technology (ART) to have biological children. Men with reduced sperm count or mobility may undergo intrauterine insemination or intracytoplasmic sperm injection, which involves depositing sperm into the uterus or injected into an egg, respectively, to increase the chance of conceiving. Male or female cancer survivors can also fertilize their sperm or eggs through in vitro fertilization (IVF) to have a child.

Survivors who lose reproductive ability after cancer and its treatment can employ third party reproduction to have children. These include using donor sperm, eggs, or embryos to have a child. Women whose bodies are unable to support a pregnancy to term can also employ a surrogate, or gestational carrier, to carry the survivor’s biological children or with the use of donor gametes. Adoption is also an option that is becoming increasingly available to cancer survivors, in part, due to some of the research at the Oncofertility Consortium. Thus, cancer patients who did not undergo fertility preservation should not lose hope as they still have the ability to build a family.

Baboon Research Paves Way for New Fertility Preservation for Cancer Patients

A section of a baboon ovary from the Xu et al. paper

Many women who preserve their reproductive potential prior to fertility-threatening cancer treatments currently choose ovarian stimulation and subsequent banking of their eggs or fertilized embryos. Unfortunately, women who choose these techniques must delay cancer treatment for up to three weeks. During that time, injectable hormones help mature follicles within the woman’s ovaries to produce oocytes which then become eggs that are retrieved during an outpatient surgery.  Since some women are not able to delay chemo- or radiation therapy, there is a need for fertility preservation that does not require hormone stimulation.

Experimental techniques such as ovarian removal and tissue banking can provide an opportunity for women to have children. One caveat of ovarian tissue banking is the risk of reintroducing the cancer when the ovary is transplanted back into the cancer survivor. Given this, researchers at the Oncofertility Consortium are developing ways to mature ovarian follicles in vitro, outside a woman’s body. Once these advances are made ovarian tissue may be removed, the follicles matured in vitro, and then go through traditional in vitro fertilization (IVF) techniques without the risk of reintroducing any cancer cells.

A recent publication by Min Xu et al. at the Oncofertility Consortium highlights advances in the in vitro culture of ovarian follicles and maturation of those follicles into oocytes. While some of these techniques are successful in rodents, the translation to non-human primates, such as baboons, has made less progress. The article, “In Vitro Oocyte Maturation and Preantral Follicle Culture from the Luteal Phase Baboon Ovary Produce Mature Oocytes,” describes how researchers are able to use the developing cells within an ovary to produce oocytes.

In the ovary, the more developed oocyte precursors, called cumulus oocyte complexes (COCs), lay underneath the outer region of the tissue, called the cortex. Xu was able to remove these COCs and mature them in vitro to produce oocytes. COCs with more layers of support cells surrounding them were more likely to mature in vitro and up to one quarter of the oocytes were then able to be fertilized by baboon sperm and begin dividing. In addition, Xu was able to remove the less mature follicles from the interior of the ovaries and culture them with a specialized growth system called a fibrin-aliginate matrix (FAM). The high-tech FAM provides support to the growing follicle but can also partially degrade and allow the follicle to expand in size as it develops into a COC. The researchers also examined the effect of follicle stimulating hormone during this growth. The detailed work published in the Biology of Reproduction provides a framework to produce new needed fertility preservation techniques for women who undergo fertility-threatening cancer therapy.

Read the entire Xu et al. article.

Fertility Preservation Patient Navigation: Tiffany’s Story

Tiffany and her husband, Dave, at a "Pre-Chemo" party the week before she started chemotherpay

Around this time last year, Tiffany found a small lump under her arm near her breast. The 28-year old knew that the lump was most-likely a benign cyst so she didn’t worry to much about it. Plus, as a typical health care consultant, she traveled Mondays through Thursdays during the week and wanted to spend weekends relaxing with her husband, not at a doctor’s office. Even as she scheduled the appointment, Tiffany was more focused on planning an upcoming spring trip to Italy and Greece than the lump. Then the tests came back. Breast cancer that had spread to her lymph nodes.

Tiffany barely remembers those first blurry days after the diagnosis. Her husband and parents came with her to the surgical consult where the physicians, “directed me to make appointments with a list of specialists including a fertility expert, medical oncologist, and genetic counselor,” she said in a recent interview at the Oncofertility Consortium. Tiffany recalls how her family scheduled appointments and helped her begin the treatment process. She soon met Kristin Smith, the oncofertility patient navigator in the Division of Fertility Preservation at Northwestern University, who explained her options. When asked about the decision-making process, Tiffany explained,” There was no choice. Of course I would do it.”

Tiffany and her husband decided to undergo embryo cryopreservation and Smith worked with the rest of the medical team to incorporate fertility treatment into the oncology schedule. According to Tiffany, “My oncologist wanted me to do chemotherapy first but knew that I wanted to undergo fertility preservation so she agreed that I could do surgery first.” After surgery, Tiffany began three weeks of hormone injections before egg extraction, fertilization with her husband’s sperm, and embryo freezing.

After completing the fertility preservation process, Tiffany underwent five months of chemotherapy and is currently more than half-way through two months of almost daily radiation and physical therapy. When reflecting on the fertility preservation process, she says, “At the time it was the littlest thing but now it is the most important,” since it gives her something to look forward to after treatment. Working with the oncofertility patient navigator Smith, “was the best part of treatment,” she says.

Though she is still in treatment, Tiffany has already begun to share her story. I first met her when she discussed her experience at an oncology nursing conference and almost brought the room to tears. She may also provide her personal perspective on fertility preservation to some of the high school students at the Oncofertility Saturday Academy. As Tiffany’s nine months of chemo- and radiation therapy come to a close in the middle of January, she is looking forward to starting her job again and, once her Tamoxifen treatment is completed, using those frozen embryos. But first there is that well-deserved European vacation…

Delivering Hope: A New Perspective on Surrogacy After Cancer

Newborn Hope, May 2001

In the late 1990s, Lauren and Henry were a young married couple looking forward to starting a family when Lauren was diagnosed with cancer. Lauren and Henry were advised by her doctors to retrieve eggs and bank embryos but the couple was still left with a dilemma. How would they find a surrogate carrier for the embryos? In the end, the couple didn’t have to look far.

Henry and his cousin Pamela were close as children but as they grew up and started their own lives they also grew apart. Married with three children, Pamela did not have a lot of time to spend with her cousin and his wife but when she heard about their plight, she knew she wanted to do something. In a recent interview with the Oncofertility Consortium, Pamela MacPhee discussed her experience carrying and giving birth to Henry and Lauren’s child. When Pamela was making that decision she wasn’t able to find information about, “the challenges of sharing a pregnancy with another couple or anything comprehensive about what to expect as a surrogate,” which led her to write a book about the story.

Delivering Hope: The Extraordinary Journey of a Surrogate Mom covers many aspects of Pamela’s experience, from dealing with painful hormone injections to forming an incredible bond with Henry and Lauren. In fact, MacPhee states, “Our relationship was the most unexpected and wonderful byproduct of the pregnancy.” Pamela gave birth to Henry and Lauren’s baby in 2001 and, as a precocious 9-year old, Hope is immensely proud of her unique birth journey. MacPhee recounted that, at an event just after the book’s release, Hope, “was there signing books with me.” MacPhee also enjoyed watching her children, then ages three, six, and eight, embrace the surrogate pregnancy. She relates that, “Kids are so good at grasping that there is more than one way to raise a family,” and have remained close to Hope since she was born.

Through the book, MacPhee recounts the personal side of the legal and bioethical issues of surrogacy that are investigated in the Oncofertility Consortium’s research. She states, “I wanted to share the message of hope of our journey,” through her book, which may help potential surrogates as they make the complex decision to provide biological children to people who have lost fertility due to cancer or its treatment.

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