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Mayo Clin Proc. Mar 2011; 86(3): 229–240.
PMCID: PMC3046944

Challenges in the Gynecologic Care of Premenopausal Women With Breast Cancer

Abstract

Premenopausal women with a new diagnosis of breast cancer are faced with many challenges. Providing health care for issues such as gynecologic comorbidities, reproductive health concerns, and vasomotor symptom control can be complicated because of the risks of hormone treatments and the adverse effects of adjuvant therapies. It is paramount that health care professionals understand and be knowledgeable about hormonal and nonhormonal treatments and their pharmacological parameters so they can offer appropriate care to women who have breast cancer, with the goal of improving quality of life. Articles for this review were identified by searching the PubMed database with no date limitations. The following search terms were used: abnormal uterine bleeding, physiologic sex steroids, endometrial ablation, hysteroscopic sterilization, fertility preservation in endometrial cancer, tranexamic acid and breast cancer, menorrhagia treatment and breast cancer, abnormal uterine bleeding and premenopausal breast cancer, levonorgestrel IUD and breast cancer, tamoxifen and gynecologic abnormalities, tamoxifen metabolism, hormones and breast cancer risk, contraception and breast cancer, pregnancy and breast cancer, and breast cancer and infertility treatment.

AUB = abnormal uterine bleeding; E2 = estradiol; EA = endometrial ablation; EC = endometrial cancer; ER = estrogen receptor; FDA = Food and Drug Administration; GnRH = gonadotropin-releasing hormone; IUD = intrauterine device; LNG = levonorgestrel; NSAID = nonsteroidal anti-inflammatory drug; PR = progesterone receptor; SHBG = sex hormone–binding globulin

Breast cancer is the leading cause of cancer death in women in the United States who are aged 20 to 59 years.1 In 2010, an estimated 207,090 new cases of breast cancer were identified in the United States.2 Although breast cancer risk increases with age, approximately 35% of breast cancers occur during the reproductive and perimenopausal years.3 The 5-year relative survival rate for women of all ages with breast cancer diagnosed between 1999 and 2005 is 89%.3 Of the premenopausal breast cancers diagnosed, approximately 58% are both estrogen receptor (ER) and progesterone receptor (PR) positive, 6% are ER positive only, 17% are PR positive only, and 20% are both ER and PR negative.4

The management and treatment of breast cancer in premenopausal women can affect menstruation, reproduction, and gynecologic health. Breast cancer treatment can have a marked affect on fertility in women who have delayed childbearing and have fewer remaining reproductive years. Among premenopausal women with breast cancer, more than 50% wish to retain their fertility.5 Additionally, other gynecologic issues and conditions are prevalent in reproductive-age women. In the general population, more than 30% of reproductive-age women fulfill criteria for the diagnosis of menorrhagia,6 25% have symptomatic fibroids,7 and nearly 67% have an underlying uterine disorder with potential to cause abnormal uterine bleeding (AUB).8

Among premenopausal women with breast cancer, management of menstrual disorders, contraception, vasomotor symptoms, and fertility presents a challenge. Common and effective hormonal options are less well studied in this population because of significant concern about recurrence of breast cancer. Herein,we present the challenges and discuss management options for young women with breast cancer who present with various common gynecologic conditions.

Articles for this review were identified by searching the PubMed database with no date limitations. The following search terms were used: abnormal uterine bleeding, physiologic sex steroids, endometrial ablation, hysteroscopic sterilization, fertility preservation in endometrial cancer, tranexamic acid and breast cancer, menorrhagia treatment and breast cancer, abnormal uterine bleeding and premenopausal breast cancer, levonorgestrel IUD and breast cancer, tamoxifen and gynecologic abnormalities, tamoxifen metabolism, hormones and breast cancer risk, contraception and breast cancer, pregnancy and breast cancer, and breast cancer and infertility treatment.

PREMENOPAUSAL SEX STEROIDS AND THEIR PHARMACOLOGY

Physiologically, premenopausal women with regular cycles have cyclic variation in levels of estradiol (E2) (15-350 pg/mL [to convert to pmol/L, multiply by 3.671]) and progesterone (0.2-27 ng/mL [to convert to nmol/L, multiply by 3.18]). These “free” (unbound) hormones are biologically active and can enter a target cell and activate its receptor.

Article Highlights

  • Management and treatment of breast cancer in premenopausal women can affect menstruation, reproduction, and gynecologic health
  • Management options for menorrhagia affecting premenopausal women with breast cancer include observation, nonsteroidal anti-inflammatory drugs, antifibrinolytics, endometrial ablation, levonorgestrel-intrauterine device, and hysterectomy
  • Among premenopausal women with breast cancer, more than 50% wish to retain their fertility, and rapid referral for fertility preservation is important because some strategies require 2 to 3 weeks to complete
  • Abnormal uterine bleeding occurs in more than 50% of women taking tamoxifen; evaluation should include endometrial sampling
  • Tamoxifen has antiestrogenic effects on the premenopausal vagina and may cause vaginal atrophy, dryness, and dyspareunia; nonhormonal management with lubricants and vaginal moisturizers should be the first-line therapy
  • Sexual dysfunction occurs in one-quarter to two-thirds of breast cancer survivors

Free E2 and progesterone levels are affected by serum carrier protein levels, with less than 2% of unconjugated steroids circulating unbound in the blood.9 The carrier proteins for sex steroid hormones are mainly sex hormone–binding globulin (SHBG) and, to a lesser degree, serum albumin.10 The bioavailability and dynamic equilibrium of sex hormones are influenced by the level of serum SHBG and other carrier proteins.11 In premenopausal women, serum SHBG, as well as E2 and progesterone levels, can be increased with tamoxifen and other selective ER modulators.12,13 Uses of estrogen and progestin preparations in the gynecologic care of premenopausal women and the effects of exogenous hormones on serum E2, progesterone, and SHBG levels are discussed subsequently.

MANAGEMENT OF AUB

Abnormal uterine bleeding includes menorrhagia (abnormally heavy or extended menstrual flow), metrorrhagia (light bleeding at irregular intervals), and intermenstrual bleeding; AUB affects nearly one-third of all reproductive-age women.6 Abnormal uterine bleeding has various anatomic and physiologic causes (Table 1). Bleeding attributable to systemic conditions, pregnancy, and medications can most often be treated by managing the underlying cause. For women with a history of breast cancer and AUB with a gynecologic cause, treatment options are limited because of the risks and fears associated with hormonal therapies and because many treatments lack evidence regarding safety and risk of breast cancer recurrence.8 Management options for AUB in premenopausal women with breast cancer are summarized in Table 2.

TABLE 1.
Causes of Abnormal Uterine Bleeding in Premenopausal Women
TABLE 2.
Management of Abnormal Uterine Bleeding in Premenopausal Women With Breast Cancera,b

AUB Caused by Anatomic Abnormalities

For the most part, AUB caused by uterine or cervical abnormalities, independent of a history of breast cancer, can be treated surgically.14,15 Benign endocervical polyps can be removed surgically, and treatment of cervical dysplasia and invasive cervical cancer is not influenced by a prior diagnosis of breast cancer. Benign endometrial polyps may be resected hysteroscopically or by dilation and curettage; hysterectomy is not necessitary. However, if endometrial cancer (EC) or complex atypical hyperplasia is detected, the standard treatment is hysterectomy.

Endometrial hyperplasia without atypia and select cases of complex atypical hyperplasia and grade 1 EC can be managed with progestin therapy if patients desire fertility preservation.16-19 The safety of systemic progestins is unknown in women with a history of breast cancer. Synthetic progestins appear to increase the risk of breast cancer development,20 but data regarding the use of medroxyprogesterone acetate in breast cancer survivors are lacking. Thus, more localized progestin therapy (eg, the levonorgestrel intrauterine device [LNG-IUD]) is a new, effective, and popular option, but patients require counseling about unknown risks of breast cancer recurrence.18

Another cause of AUB is uterine fibroids, which are clinically apparent in up to 25% of women.7 Many treatment options are available for symptomatic fibroids. Submucosal fibroids can be resected hysteroscopically, depending on the size and amount of fibroid in the cavity. Larger intramural fibroids can be treated through myomectomy for women who desire fertility; focused ultrasonographic therapy is also an option if patients are counseled about the limited but promising fertility data.21-23 Uterine artery embolization and hysterectomy are effective treatments that are recommended for women who have completed childbearing.24,25

AUB Associated With Anovulatory Cycles

Anovulatory cycles are caused by a disturbance of the normal hypothalamic-pituitary-ovarian axis, resulting in an absent luteal phase and failure of the ovary to produce the increased progesterone levels needed for endometrial stabilization. The E2 serum levels in anovulation remain consistent with E2 levels normally associated with proliferative-phase endometrium.26 As the endometrium proliferates without a secretory phase, irregular bleeding ensues, and untreated proliferation can lead to endometrial hyperplasia or EC. An endometrial biopsy is necessary to exclude malignancy. Standard treatment for anovulatory bleeding is systemic hormones—oral, transdermal, or vaginal combined estrogen and progestin preparations.27 Among women with a history of breast cancer, systemic hormones are of concern because they may increase the risk of breast cancer recurrence.28 Management options include (1) observation with periodic endometrial biopsies, (2) LNG-IUD in select women who wish to preserve fertility, or (3) hysterectomy.

Management of Menorrhagia. Women with menorrhagia should undergo an endometrial biopsy to exclude malignancy. If no disease is evident, management of menorrhagia may include the following: (1) observation, (2) nonsteroidal anti-inflammatory drugs (NSAIDs), (3) antifibrinolytics, (4) endometrial ablation (EA), (5) LNG-IUD, and (6) hysterectomy.

NSAIDs such as ibuprofen, naproxen, and mefenamic acid improve menorrhagia by blocking cyclooxygenase, which converts arachidonic acid to prostaglandins.29 Prostaglandin F2α is elevated in the endometrium of women with menorrhagia compared with those without menorrhagia.30 Additionally, NSAIDs increase uterine vasoconstriction and platelet aggregation. In a Cochrane Review,31 NSAID use significantly improved bleeding compared with placebo but was not as effective as LNG-IUDs or tranexamic acid. NSAID treatment is initiated just before the onset of menses and continued for approximately 5 days; adverse effects such as abdominal pain, nausea, gastric bleeding, and ulcer development29 are reduced because the medications are taken cyclically; nevertheless, precautions should be taken. Additional benefits of NSAID use include improvement of menstrual cramps and pain.

Tranexamic acid, a fibrinolytic inhibitor, has been used extensively in Europe for treatment of menorrhagia but was approved only recently by the US Food and Drug Administration (FDA). The mechanism of action is inhibition of the conversion of plasminogen to plasmin; this blocks fibrinoly sis in the endometrium. Multiple studies have demonstrated a 40% to 54% decrease in bleeding,29,32 but tranexamic acid does not manage menstrual cramps as effectively as NSAIDs. Potential concerns about an increased thrombosis risk have been evaluated, and the rate of thrombosis associated with tranexamic acid use appears similar to that of the general population.32,33 Tranexamic acid reduces wound complications during breast cancer surgery when it is used at doses similar to those for menorrhagia34; however, no data have been published on long-term use in women with breast cancer.

As an effective, minimally invasive, localized treatment for menorrhagia, EA can be performed using electrocautery, laser, cryotherapy, thermal balloon, heated saline, microwave, or radiofrequency techniques. Both thermal balloon ablation and radiofrequency ablation decrease menstrual blood loss by approximately 90% in the first 3 years after treatment, and the rate of amenorrhea after radiofrequency ablation is more than 30%.35 Women older than 45 years, with a small uterus and thin lining, have the highest risk of amenorrhea.36 Failure of EA is associated with preoperative dysmenorrhea or tubal ligation.36 Although EA does not appear to increase the risk of EC,37,38 EC can occur after ablation. Endometrial cancer is associated with type II diabetes mellitus, obesity, hypertension, colon cancer, anovulatory syndromes such as polycystic ovarian syndrome, history of endometrial hyperplasia, and failure of progestin treatment of any cause of AUB.38,39 Patients considering EA should be counseled appropriately, and EA should be avoided in patients with high risk of EC. Patients must be counseled about the lower likelihood of successful endometrial biopsy, if it is indicated after EA.40

In 2009, the LNG-IUD was FDA approved for the treatment of menorrhagia.41 The device is a T-shaped polyethylene frame with a reservoir containing 52 mg of the progestin LNG. The initial dose, released daily into the uterine cavity, is 20 μg. This dose gradually decreases; by 5 years, the daily dose is approximately 10 μg. The effect of the LNG-IUD is primarily within the uterus. It causes stromal pseudodecidualization, glandular atrophy, decreased glandular and stromal mitoses, and leukocytic infiltration.42 The LNG-IUD appears to have minimal effects on ovulation and breast milk production and does not markedly affect serum levels of E2, progesterone, or luteinizing hormone.42,43 However, LNG is one of the most potent progestins and has high binding affinity for PRs.44 In addition, LNG strongly binds SHBG and lowers serum SHBG levels.43 Use of the LNG-IUD has been associated with increased incidence of gallbladder disease (relative risk, 1.5), hypertension (relative risk, 1.8), headache, malaise, weight change, anxiety, depression, arthropathies, upper-limb neuropathies, and minor visual disturbances.45 Thus, although some reproductive functions appear to be unaffected, LNG administered via an IUD does seem to have systemic effects.

Population-based studies of premenopausal women have shown that the LNG-IUD, used either for AUB or contraception, does not increase the risk of breast cancer.46,47 In addition, when used by premenopausal women after initiation of breast cancer treatment, the LNG-IUD does not appear to increase the risk of breast cancer recurrence.48 Thus, for premenopausal women who wish to retain fertility but have menstrual disturbances, the LNG-IUD seems to be a reasonable, short-term treatment. In postmenopausal women, the LNG-IUD should be removed. One case-control study of women aged 50 to 62 years showed that the risk of a new breast cancer diagnosis was 1.5 times higher in women using the LNG-IUD alone and was 2 times the baseline risk when combined with either transdermal or oral estrogen replacement.49

TAMOXIFEN USE AND AUB

Tamoxifen is an FDA-approved, nonsteroidal, selective ER modulator that is indicated for 5 years of therapy for chemo-prevention among women with increased risk of breast cancer and adjuvant treatment in premenopausal and postmenopausal women with hormone-sensitive breast cancer.50 Tamoxifen is a competitive inhibitor of estrogen; it binds to ERs51 in the breast and blocks tumor proliferation.51,52 In postmenopausal women, tamoxifen has an estrogen-agonist property and can stimulate endometrial proliferation, resulting in atypical hyperplasia and EC. Tamoxifen use increases symptomatic endometrial disease by nearly 27% within 2 years of initiation of treatment53; for these patients, the relative risk of EC is 2.2 to 4 compared with population-based rates of EC.54,55 However, tamoxifen has an antiestrogenic effect on the premenopausal endometrium,56-58 and asymptomatic premenopausal women who take tamoxifen do not appear to have increased risk of polyps, hyperplasia, or EC.58,59

Abnormal uterine bleeding occurs in more than 50% of premenopausal women taking tamoxifen,58,60 and in this group of women, up to 23% will have an underlying endometrial abnormality such as polyps, hyperplasia, or EC. However, the incidence of endometrial disease is not markedly different compared with that in premenopausal women with breast cancer and AUB who are not taking tamoxifen.60,61 This supports the notion that tamoxifen does not increase the risk of EC and its precursors in premenopausal women. Additionally, nearly half of all premenopausal women treated with tamoxifen will have intermittent or long-term amenorrhea or oligomenorrhea57,58,60; therefore, menstrual history in this group of women is an unreliable indicator of menopausal status.58 Caution must be exercised in premenopausal women who become amenorrheic while taking tamoxifen, and clinical menopause should be confirmed with serum hormone levels. Both E2 and follicle-stimulating hormone levels remain reliable endocrinologic markers in the setting of tamoxifen use.58 Amenorrheic women with low serum E2 levels may have entered menopause and are at an increased risk of EC development.62

Given the higher rate of endometrial disease in premenopausal women taking tamoxifen who have development of AUB, further evaluation is warranted via endometrial sampling with an office biopsy or with operative curettage (with or without hysteroscopy).61 Although dilation and curettage is the criterion standard, an office biopsy with an endometrial suction curette is comparable to dilation and curettage, with up to 88% sensitivity, 100% specificity, 100% positive predictive value, and 98% negative predictive value.63 Furthermore, it is 95% accurate in detecting endometrial abnormalities in symptomatic premenopausal women taking tamoxifen.64 If endometrial sampling shows benign pathologic findings, recurrent AUB can be observed and followed up with periodic endometrial sampling to exclude endometrial disease.

For women with AUB, the LNG-IUD appears to be safe to use in conjunction with tamoxifen48; however, for irregular or intermittent bleeding in the setting of amenorrhea, premenopausal status should be confirmed before placement. The LNG-IUD does not protect against complex atypical hyperplasia or EC associated with postmenopausal tamoxifen use,65-67 and it should be removed when a woman reaches menopause.

Women taking tamoxifen should be counseled carefully when considering EA. Residual endometrium is present after EA, and a post-EA uterine cavity assessment with an office biopsy or sonohysterography is unsuccessful in one-quarter of women.40 In addition, although EA does not appear to increase the risk of EC,37,38 EA in the context of tamoxifen use has not been well studied. Definitive management via hysterectomy can be considered for women who have uncontrolled AUB associated with tamoxifen use and have completed their childbearing. Management of tamoxifen and other treatment-related sequelae is summarized in Table 3.

TABLE 3.
Breast Cancer Treatment–Associated Gynecologic Sequelae and Management Options

Endometrial thickness (assessed by transvaginal ultrasonography) has been well studied in postmenopausal women, and the likelihood of EC increases with endometrial thickness greater than 5 mm.68,69 However, endometrial thickness has not been well studied in premenopausal women. In premenopausal women taking tamoxifen, endometrial thickening has been defined in the literature as greater than 8 mm to greater than 12 mm,58,64 but neither occult hyperplasia nor EC has been reported in screened, asymptomatic premenopausal women (premenopausal status was endocrinologically proven) who had a thickened endometrium while taking tamoxifen.58 Thus, screening with transvaginal ultrasonography appears to have low yield in this low-risk population of women.

CONTRACEPTION DURING AND AFTER BREAST CANCER TREATMENT

Pregnancy is not recommended during systemic cytotoxic chemotherapy, during tamoxifen therapy, or for 2 months after completion of tamoxifen therapy.70 Although premenopausal women treated with chemotherapy have an increased risk of premature ovarian failure, an alternative method of contraception is still required until menopause is confirmed.71,72

Those who have completed their childbearing should be counseled about permanent contraceptive options. Failure rates of permanent contraceptive methods, natural family planning, and barrier methods are listed in Tables Tables44 and and5.5. The more effective nonhormonal or hormonal methods with limited systemic effects may be more attractive to some women. Contraceptive options for women with a history of breast cancer are shown in the Figure.

TABLE 4.
One-Year Failure Rates for Permanent Contraceptive Methods
TABLE 5.
One-Year Failure Rates for Barrier Contraceptive Methods
FIGURE.
Contraception algorithm for premenopausal women with breast cancer. BSO = bilateral salpingo-oophorectomy; IUD = intrauterine device.

Although systemic hormones are the most common reversible contraceptive methods, they are not recommended for women with a history of breast cancer. Intrauterine devices are highly effective, with rates of pregnancy after 1 year of typical use at 0.8% for copper IUDs and 0.2% for LNG-IUDs.77 The current FDA-approved copper IUD (ParaGard, Duramed Pharmaceuticals, Inc, Pomona, NY) remains in place for 10 years. It is associated with high patient satisfaction, similar to that with the LNG-IUD,78 which was FDA-approved for contraception in 2000 and can remain in place for 5 years. The copper IUD may be associated with a higher rate of abnormal bleeding.79 In women with a history of AUB or risk factors for AUB, the LNG-IUD may be preferred.

Permanent sterilization can be performed laparoscopically, hysteroscopically, transvaginally, or concurrently with any abdominal surgery. The hysteroscopic methods Essure (Conceptus Inc, Mountain View, CA) and Adiana (Hologic, Inc, Bedford, MA) are performed as outpatient surgical procedures, and patients usually are able to return to work the next day. The Essure procedure uses 4-cm long nickel-titanium coils that are placed into the fallopian tubes.80 In the Adiana procedure, a radiofrequency ablation creates a lesion at the isthmus of the fallopian tube, and a silicone matrix is then injected at the site. For both methods, tissue in-growth occludes the tubes in a 3-month period. Patients will need a back-up method of contraception during that period.81 A hysterosalpingogram is obtained after 3 months to confirm bilateral tubal occlusion.

Laparoscopic methods of tubal ligation include Filshie clips (Cooper Surgical, Trumbull, CT), cauterization, suture ligation, or removal of a portion or all of the fallopian tubes bilaterally. These outpatient procedures require 2 to 4 small incisions in the abdomen and have a postoperative recovery time of about 1 week. Bilateral salpingectomy can also be performed via a vaginal culdotomy.82 These methods are immediately effective and do not require back-up contraception or a hysterosalpingogram. For women with a BRCA mutation, bilateral salpingo-oophorectomy provides permanent sterilization and reduces the risk of ovarian cancer.83

FERTILITY AFTER BREAST CANCER

Reproductive-age women with cancer diagnoses are highly concerned about future fertility; approximately three-quarters of women younger than 35 years who are childless at cancer diagnosis want to preserve their fertility.84 Although potentially life-saving, cancer therapy can result in subfertility or even sterility because of permanent germ cell damage. In 2006, the American Society of Clinical Oncology recommended that oncologists discuss the possibility of infertility with reproductive-age cancer patients and offer referral for fertility preservation consultation and therapy.85 Rapid referral is essential because some strategies require 2 to 3 weeks to complete; ideally, fertility-preserving procedures can be performed between surgery and the start of adjuvant therapy.

Fertility preservation options (Table 3) vary by age, type of malignancy, and anticipated cancer treatment. For example, alkylating agents, which are non–cell-cycle-specific, are associated with the highest risk of ovarian failure. The odds ratio for inducing complete ovarian failure with the alkylating agent cyclophosphamide is 3.98 compared with unexposed women.72 Age is also a critical factor; in 1 study, the incidence of amenorrhea after chemotherapy in women who received cyclophosphamide, methotrexate, and 5-fluorouracil was 61% for women younger than 40 years and 95% for those older than 40 years.71 Rates of amenorrhea after common adjuvant chemotherapy regimens for breast cancer are outlined in Table 6.71,86-89

TABLE 6.
Amenorrhea Associated With Breast Cancer Adjuvant Chemotherapy Regimens Commonly Used in the United States

At the initial consultation, the patient's risk of fertility impairment should be discussed, taking into account the patient's current ovarian function, family-building goals, and planned cancer therapy. Current fertility preservation options include established and experimental strategies. Established therapies include standard assisted-reproductive technologies such as in vitro fertilization. For patients undergoing in vitro fertilization, exogenous gonadotropins are given to induce a cohort of immature oocytes to synchronously develop, a process typically requiring 10 to 12 days. Endogenous estrogen levels become supraphysiologic during ovarian stimulation, raising concerns about excess hormone exposure in women who may already have a hormone-sensitive malignancy. However, the elevation in estrogen levels is brief (<3 weeks), and levels rapidly return to baseline. Special stimulation protocols using aromatase inhibitors also have been developed to limit estrogen exposure.90 Breast cancer patients who undergo ovarian stimulation and embryo cryopreservation do not appear to have an increased risk of disease recurrence or death.91

After ovarian stimulation, mature oocytes are harvested and can be cryopreserved immediately in an unfertilized state or they can be fertilized to create embryos that are subsequently frozen. Cryopreserved embryos and oocytes can be used years or even decades after the initial freezing. Frozen embryos have more uniform cellularity than unfertilized oocytes and thus survive the freeze-thaw process better than oocytes. Although laboratory-specific rates vary, greater than 90% of embryos can survive the thawing process compared with approximately 50% to 60% of cryopreserved oocytes. Pregnancy rates also vary by the type of procedure performed and by oocyte age. For women younger than 35 years, pregnancy rates after the transfer of thawed embryos approach 50%, whereas those from frozen oocytes are considerably lower (10%-20% at best). Thus, some centers consider oocyte cryopreservation to be an experimental therapy. When feasible, most women considering oocyte or embryo cryopreservation are counseled toward embryo creation, even if it requires donor sperm purchased from a commercial sperm bank.

For women without sufficient time or resources or who are unwilling to undergo embryo or oocyte cryopreservation, other fertility preservation options include medical ovarian suppression and cryopreservation of ovarian tissue. Ovarian suppression is primarily achieved by administering gonadotropin-releasing hormone (GnRH) agonists to temporarily suppress the hypothalamic-pituitary-ovarian axis. Adverse effects of GnRH agonists include hot flashes and vaginal dryness. Bone density may decrease if GnRH agonists are given for an extended period (>6 months). A recent, prospective, randomized study of concurrent GnRH agonist use during chemotherapy in premenopausal women with breast cancer92 showed that nearly 90% of women treated with GnRH agonists resumed menses and 69% resumed spontaneous ovulation after treatment. In contrast, of women who received chemotherapy only, 33.3% resumed menses, and 25.6% resumed spontaneous ovulation.

Ovarian tissue cryopreservation requires surgery to remove one or both ovaries. Ideally, oophorectomy is performed as an outpatient surgical procedure before chemotherapy or radiotherapy; in some cases, it may be performed in conjunction with breast cancer surgery. The ovarian cortex is dissected into thin strips and frozen. Thawed oocytes potentially could be fertilized to create embryos that are transferred into the uterus of the patient or a gestational carrier. In experimental conditions, ovarian tissue strips have been transplanted back into orthotopic or heterotopic sites with rare reports of subsequent pregnancies. Of note, however, fewer than 10 births worldwide have been reported to date from cryopreserved ovarian tissue.93

EFFECT OF PREGNANCY

Historically, the protective effect of pregnancy against breast cancer has been attributed to the full epithelial differentiation within the breast because of lactation. However, newer evidence suggests that the protective effect may be short-term tissue exposure to pregnancy-level estrogen.94 Physiologically, endogenous hormones contribute to development of the terminal ductal lobular unit in the breast—the site of origin for both benign and malignant breast tumors that result from cellular proliferation.95 Pregnancy accelerates the development and maturity of terminal ductal lobular units.95 Although parity is protective, epidemiologic studies have shown a transient increase in the risk of a new breast cancer diagnosis in the 10 years after a woman's final pregnancy.96,97

The risk of breast cancer recurrence does not appear to increase with pregnancy after breast cancer treatment.98-101 A large Danish study of 371 women who were pregnant after breast cancer showed no increase in the risk of cancer recurrence or worsening of prognosis with pregnancy.102 In fact, women with full-term pregnancies had a reduced risk of death. Additionally, the risk of recurrence did not appear to increase,98-101 and the 5-year survival rate was 100% when the pregnancy occurred 1 to 2 years after treatment.103,104 However, caution must be used when interpreting the results because a “healthy mother effect” may exist—that is, only the healthier breast cancer survivors may attempt to conceive.

LOW LIBIDO AND SEXUAL DYSFUNCTION

Multiple studies have shown that breast cancer can negatively affect sexual function. Sexual dysfunction occurs in approximately one-quarter to two-thirds of breast cancer survivors.105 Women who receive chemotherapy appear to be more negatively affected than those who do not.105 Other factors that affect sexual function include vaginal dryness and lower perceived sexual attractiveness.106 Sexual problems appear to be markedly more severe in the immediate postsurgical period; although they diminish with time, they are still more severe 1 year after treatment than before diagnosis.106 Treatment of low libido (Table 3) is complex, and few medical options currently exist. Working with a qualified sex therapist to address self-image and relationship issues is a critical component in the treatment of sexual dysfunction.

Studies that have examined the use of testosterone for low libido in women who enter menopause naturally or surgically have shown modest increases in sexual desire or activity (or both). Many of these studies were performed in women who received concomitant estrogen therapy.107-111 Safety data are limited; long-term effects of testosterone, including effects on the breast, are unknown. Thus, applicability of testosterone is limited in women who have a history of breast cancer and in women who are unable to receive estrogen therapy.

MANAGEMENT OF VULVOVAGINAL ADVERSE EFFECTS ATTRIBUTABLE TO ANTIESTROGEN THERAPY

Tamoxifen and other selective ER modulators have antiestrogenic effects on the premenopausal vagina (similar to their effect on the endometrium); these may cause vaginal atrophy and dryness, dyspareunia, and urinary urgency and frequency.112,113 Management options are listed in Table 3. Nonestrogenic treatments such as nonhormonal lubricants and vaginal moisturizers should be first-line therapy for women with a history of breast cancer because they have been shown to improve blood flow to vulvovaginal tissue and improve dryness.114,115

Once-daily treatment with vaginal estrogen preparations (Vagifem E2 tablet, Novo Nordisk, Princeton, NJ) and Premarin conjugated estrogen cream (Pfizer, Inc, New York, NY) has been studied in postmenopausal women. Women applied either a 25 μg E2 tablet or 1 g of conjugated estrogen cream (containing 0.625 mg estrogen) daily to the vagina for 1 week. Among women receiving vaginal E2, a 6.4-fold increase in serum E2 levels was observed (pretreatment mean [SD], 3.12 [0.83] pg/mL; posttreatment, 19.83 [6.07] pg/mL). Among women using conjugated estrogen cream, a 4.2-fold increase in E2 was observed (pretreatment, 2.79 [0.31] pg/mL; posttreatment, 11.63 [0.95] pg/mL),116-119 confirming systemic absorption. These findings have raised concerns about the safety of vaginal estrogen in breast cancer survivors. However, serum E2 levels in postmenopausal women receiving vaginal estrogen preparations are similar to the lowest serum E2 levels in premenopausal women with regular cycles. Vaginal estrogen has not been shown to increase the risk of breast cancer recurrence in postmenopausal women, but long-term, large-scale studies showing safety are lacking.117

A more acceptable and desirable option would be use of lower-dose vaginal estrogen tablets with less frequency (once per week rather than twice per week) along with the regular use of nonhormonal lubricants.120 Newer agents such as the E2 10-μg vaginal tablet (Vagifem) and the silastic 17-β-estradiol impregnated slow-release vaginal ring (Estring, Pfizer, Inc, New York, NY) are also FDA approved for vaginal atrophy and are associated with significantly lower systemic E2 concentrations.121,122 Until further studies that assess long-term safety are available, localized estrogen for management of vulvovaginal atrophy remains controversial. The decision to use estrogen therapy for a woman with a history of breast cancer requires consultation with the patient's oncologist and consideration of the patient's personal values and desire to balance risks against quality of life.

MANAGEMENT OF VASOMOTOR SYMPTOMS

Various nonpharmacological, alternative, nonhormonal, and hormonal therapies are used for management of vasomotor symptoms (Table 3). Systemic hormone replacement is relatively contraindicated in women with breast cancer because of the increased risk of cancer recurrence.28 Although no placebo-controlled, randomized clinical trials of non-pharmacological or alternative approaches have been performed, nonpharmacological approaches such as avoiding hot flash triggers (eg, alcohol, hot drinks, and smoking), wearing loose-fitting clothing, and exercising are effective for many women. Additionally, behavioral modifications such as a healthy diet, paced respiration, meditation, biofeedback, and applied relaxation can be helpful.123

Alternative methods include acupuncture and herbal remedies. Prospective randomized trials have shown little or no improvement in hot flashes after use of soy preparations, red clover, dong quai, ginseng, primrose oil, and black cohosh compared with placebo treatment.124,125 In addition, the FDA does not regulate most alternative medicine remedies—doses and ingredients may vary widely. Derivatives of soy and red clover include phytoestrogens and their effect on breast cancer survivors with ER-positive tumors remains inconclusive.126-128

Nonhormonal pharmacological approaches include selective serotonin reuptake inhibitors and selective noradrenergic reuptake inhibitors. Compared with placebo, medications such as paroxetine, fluoxetine, sertraline, and venlafaxine were associated with significant improvement in hot flashes.129,130 The most effective oral doses appear to be as follows: paroxetine, 10 to 25 mg/d; fluoxetine, 20 mg/d; sertraline, 100 mg/d; and venlafaxine, 75 mg/d.131,132 Gabapentin, at oral doses ranging from 900 to 2400 mg/d, also significantly reduced hot flashes compared with placebo.123,130,131

Women who take tamoxifen should avoid medications that inhibit the CYP2D6 enzyme, which is responsible for the metabolism of tamoxifen to its active metabolite, endoxifen. Specifically, tamoxifen, sertraline, paroxetine, and fluoxetine all inhibit the activity of the cytochrome P450 (CYP) 2D6 enzyme. This interaction is not observed with venlafaxine.132 The interactions between tamoxifen and medications that interfere with CYP2D6 enzyme activity may result in treatment failure and subsequently may increase risk of breast cancer recurrence.133

CONCLUSION

Many young survivors of breast cancer are seeking options for management of menstrual abnormalities, fertility, family planning, and vasomotor symptoms; such patients may benefit from appropriate counseling and referral to gynecologic and breast health specialists. The clinical dilemma of balancing the risk of breast cancer recurrence with symptoms and quality of life can be challenging for health care professionals and patients. Health care professionals can benefit from understanding available new technologies and their potential to markedly affect and improve the quality of life of premenopausal women who survive breast cancer.

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