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. 2015 Mar 25;92(5):133. doi: 10.1095/biolreprod.115.128207

Challenges and Potential for Ovarian Preservation with SERMs1

Alison Y Ting 4, Brian K Petroff 3,2
PMCID: PMC4645985  PMID: 25810474

Abstract

Tamoxifen (TAM) is a selective estrogen receptor modulator with tissue-specific effects on estrogen signaling used predominantly for treatment and chemoprevention of breast cancers. Recent studies have shown that TAM prevents infertility and decreases follicular loss from common cancer chemotherapy and radiation therapy in preclinical models. Here we review current and novel uses of selective estrogen receptor modulator s and advantages and challenges for translation of TAM for human fertility preservation.

Keywords: cancer, fertility, ovary, SERM, tamoxifen

INTRODUCTION

Recently published preclinical studies demonstrate effective prevention of ovarian toxicity and infertility from cancer chemotherapy drugs and therapeutic radiation using the selective estrogen receptor modulator (SERM) tamoxifen (TAM) as a medical countermeasure [1–3]. This has prompted calls for translation of TAM as an alternative or adjunct to embryonic cryopreservation for fertility preservation in premenopausal women and girls [3]. Here we review the background for this problem, discuss novel uses of SERMs, including as countermeasures to toxicants and drug resistance, and integrate these studies with current clinical indications for TAM.

Current Fertility Preservation in Women and Girls with Cancer

The need for improved fertility in cancer survivors has been recognized repeatedly and reflects improvements in cancer survival. Nearly one million girls and premenopausal women are diagnosed with cancer each year worldwide [4–6]. Standard combination cancer chemotherapy and bone marrow transplantation often cause female infertility and premature menopause [7–9]. The incidence of ovarian failure following cancer treatment varies widely with age and chemotherapy and radiotherapy treatment regimens. Advancing age, dose intensity, cyclophosphamide (Cy), bone marrow transplantation, and abdominal radiation regimens in particular predispose the patients to prolonged amenorrhea following therapy [10–13]. On average, 70% of premenopausal patients receiving alkylating chemotherapy experience prolonged or permanent amenorrhea after treatment [10]. Amenorrhea is less common, but still significant, for other chemotherapy regimens. The impact of cancer chemotherapy on the long-term health of aging women [14] remains largely unaddressed in the literature, but premature menopause is detrimental and associated with heart disease, osteoporosis, stroke, and/or neurological dysfunction [15]. It is important when considering the impact of cancer treatment on fertility to distinguish acute effects of chemotherapy on ovarian function from long-term sequelae such as premature ovarian failure [16].

Embryonic cryopreservation is the current standard of care for fertility preservation in women with cancer wanting children in the future. There are many advantages to this approach. The embryo is removed from exposure to antineoplastics and can be stored for a long period of time for future transfer to the cancer survivor when desired [17, 18]. Over a million children have been born worldwide from cryopreserved embryos. However, this technology requires treatment delay (2–6 wk) and a current partner, is invasive, and fails to protect future ovarian function [19]. Oocyte cryopreservation provides patients without a current partner one method to preserve reproductive potential. Cryopreservation of mature oocytes is no longer considered experimental by the Practice Committees of the American Society for Reproductive Medicine and the Society for Assisted Reproductive Technology [20]. Studies showed no evidence of neonatal risk, chromosomal abnormalities, birth defects, or developmental deficits in babies born from cryopreserved oocytes [21, 22]. Similar to embryo cryopreservation, however, oocyte cryopreservation requires treatment delay and surgical procedures, and does not preserve normal ovarian function. For patients who are prepubertal or require immediate aggressive cancer therapy, ovarian tissue cryopreservation is an option for future fertility [23]. Autografting of frozen-thawed ovarian tissue then provides the only option for restoring ovarian endocrine function and has been shown to induce puberty [24]. However, this technology is still experimental, with only 24 live births born from cryopreserved ovarian tissue [25] since the first case was reported in 2004. Additionally, the infrastructure and high cost associated with cryopreservation limit its widespread use. Because of this, only a small proportion of eligible women seek to avoid reproductive side effects from cancer treatment using this approach.

Alternatives to Cryopreservation for Fertility Preservation in Women with Cancer

Medical countermeasures to ovarian toxicity from cancer treatment have been explored experimentally in females for decades. Broadly speaking, these agents have either been ovarian suppressants or antiapoptotic drugs. Initial attempts used contraceptives to promote ovarian quiescence in an effort to decrease losses of growing ovarian follicles from chemotherapy [26], and there is some evidence of potential benefit in lymphoma patients from this approach [27]. Numerous preclinical and human trials have tested gonadotropin-releasing hormone (GnRH) antagonists for ovarian suppression with mixed results [28–32]. Most recently, Albain and colleagues observed a small but significant increase in posttreatment fertility in estrogen receptor (ER)-negative breast cancer patients supplemented with a GnRH antagonist in the Prevention of Early Menopause Study trial [33]. Importantly, this fertility benefit was accompanied by increased survival, and ER-negative disease is more prevalent in premenopausal women.

Glutathione and sphingosine-1-phosphate are antiapoptotics that have been shown preclinically to decrease follicle loss from antineoplastics and other toxicants [34]. Sphingosine-1-phosphate is the metabolite of ceramide, a sphingolipid second messenger and conserved mediator of germ cell death. These agents do require local ovarian delivery to avoid negative interaction with cancer treatment, but this approach has been demonstrated successfully using a nonhuman primate model [35].

Imatinib, a tyrosine-kinase inhibitor, is commonly used for treatment of chronic myeloid leukemia by inhibiting proliferation and promoting apoptosis in cancer cells. Imatinib targets tyrosine-kinases including BCR-ABL, c-Abl, platelet-derived growth factor (PDGF), receptor as well as c-kit. All of these are associated with cell differentiation, cell division, cell adhesion, and stress response. PDGF and c-kit are expressed in ovarian follicles [36]. Some studies have shown that imatinib can decrease apoptotic follicle loss and infertility resulting from cisplatin and doxorubicin (DOX) [37, 38], but another study contradicts this finding [39]; thus far, imatinib does not appear to affect ovarian toxicity from other agents [38].

Tamoxifen as an Ovarian Protectant

We first observed ovarian protection with TAM incidentally during a preclinical cancer prevention study using 7,12-dimethylbenz [α] anthracene, an experimental carcinogen and ovarian toxicant, to induce ovarian cancer [40]. Although TAM failed to affect ovarian tumorigenesis, TAM-treated rats had greater ovarian follicular reserves than those receiving 7,12-dimethylbenz [α] anthracene alone. In a subsequent study focused on reproductive endpoints, TAM prevented follicle loss and restored fertility in rats receiving Cy regimens that mimic cancer chemotherapy (Fig. 1, adapted from [1]). TAM also improved health and viability of rat cumulus-oocyte-complexes when given with DOX in vitro (Fig. 2, adapted from [1]). Recent work characterized ovarian protection by TAM in vitro. These studies revealed that TAM exerts local antiapoptotic effects in the ovary, and the follicular rescue with TAM was associated with decreased expression of genes related to inflammation [41]. This in vitro study of TAM has established that local ovarian mechanisms of TAM are sufficient for follicular rescue in rodents.

FIG. 1.

FIG. 1

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A) Hematoxylin and eosin-stained sections of the ovary from rats exposed to vehicle (CONT), cyclophosphamide (Cy, 50 mg/wk), tamoxifen (TAM), or Cy + TAM for 2 wk. Arrowheads = primordial follicles; arrows = primary follicles. Cy decreased follicular reserves compared to CONT, and the addition of TAM inhibited this depletion. TAM alone elevated the number of follicles compared to CONT. Bar = 50 μm. B) Numbers of primordial follicle loss relative to CONT. Average number of follicles per ovary in CONT was 6.1 × 103. Cy at 35 and 50 mg/kg/wk induced follicles loss compared to CONT, and the addition of TAM to both doses of Cy inhibited this depletion. TAM alone did not affect follicle numbers. Different letters indicate significant differences among different treatment groups. Adapted from Ting and Petroff (2010) [1] with permission.

A similar protective effect of TAM on ovarian reserve was also observed by others. Mahran and colleagues demonstrated improved fertility and expanded follicular reserves when using TAM as a countermeasure for ovarian toxicity resulting from therapeutic irradiation in rats [2]. Mechanistically, the most salient feature of this study was the finding that insulin growth factor-1 (IGF-1) receptor was upregulated in the ovary in response to TAM. IGF-1 has been shown previously to play a role in early stage follicle survival in human [42] as well as stimulating granulosa cell function in human and rodents [43, 44]. In addition, IGF-1 is upregulated by ionizing radiation in other tissues [45, 46], but the necessity of this pathway for follicular rescue with TAM remains unknown.

Mechanisms of SERM Action

TAM and other SERMs have a complex and only partially understood mechanism of selective, tissue-specific activation or inhibition of estrogen signaling. The current working model of SERM action and selectivity [47] encompasses 1) competition with endogenous estrogens for ER binding sites, 2) differential affinity and effect of ER isoforms α and β, with α being generally proliferative and β signaling less so, and 3) formation of an altered conformation of the bound receptor in comparison to the natural estrogen ligand leading to altered affinity for estrogen response elements on regulated genes and/or altered recruitment of ER coactivators (for estrogenic SERM actions) or corepressors (for antiestrogenic SERM actions). Of course, it follows that the action of a SERM upon a particular cell type or organ is determined in large part by the complement of ER isoforms, ERE polymorphisms, corepressor, and coactivator plentitude or scarcity and existing concentrations of endogenous estrogens. TAM is largely antiestrogenic in breast tissue while exerting agonistic estrogen-like actions on bone and in the uterus [48]. The impact of TAM on ovarian estrogen signaling is particularly complex because any direct ovarian action is combined with increased gonadotropin stimuli in premenopausal females due to loss of hypothalamic estrogen feedback signaling and because local concentrations of estrogens are remarkably high in the premenopausal ovary [49].

Direct TAM Actions on the Ovary

TAM induces apoptosis in cultured luteal cells in association with elevated bax, bcl-2, and c-myc [50]. Estradiol (E2) and TAM have opposing effects on inhibin expression by rodent granulosa cells in vitro [51], suggesting an antiestrogenic effect of TAM in the ovary, at least for this endpoint. Estradiol-arrested proliferation of granulosa cells not primed with gonadotropin in vitro and TAM reversed this effect [52]. In contrast, both TAM and E2 suppress luteal progesterone production by porcine granulosa cells in vitro [52]. TAM and E2 both suppress proliferation and increase apoptosis of primate ovarian surface epithelium [53]. In vivo, TAM is sometimes used to induce human follicular development in assisted reproductive technology protocols, and such use does not appear to be associated with changes in oocyte quality or maturation [54, 55]. Estradiol has been suggested to act locally in the ovary to increase intercellular communication and gap junction expression in follicular cells and decrease granulosa cell apoptosis [56]. Alteration of these mechanisms of follicular loss and drug exposures are potential mechanisms of follicular rescue by TAM that remain to be tested.

Protective Actions of TAM in Other Tissues

TAM also exerts protective effects in other tissues. Most prominently, TAM decreases tissue damage and loss of function in animal models of spinal cord injury [57, 58] and traumatic or ischemic brain injury [59, 60]. This neuroprotective effect of TAM was associated variously with decreased inflammatory signaling, beneficial redox alterations, increased expression of channel proteins to decrease edema, and diminished NF-KB effects. Interestingly, these benefits from TAM are mimicked by E2 in these tissues [58].

Current Clinical Application of TAM

Therapeutic investigation of TAM has focused on its antagonism of proliferative mammary ER signaling that results in regression of ER-positive breast cancers and reduces the incidence of ER-positive disease by up to 50% when used for prevention of breast cancer in healthy women at increased risk of the disease [61, 62]. Indeed, TAM offers long-term (10-plus yr) benefit against breast cancer [63]. In addition to this established antihormonal benefit, a number of studies have documented, and attempted to exploit in clinical trial, the ability of TAM to reverse multidrug resistance and improve medical outcome. Multidrug resistance to chemotherapy is a major factor in treatment failure and remains a major challenge in cancer therapy [64]. Overexpression of cell membrane pumps, including p-glycoprotein/multidrug resistance-associated proteins, are often found in cancer cells and are responsible for pumping chemotherapy drugs out of the cell, resulting in multidrug resistance [65]. Studies have shown that coadministration of TAM and chemotherapy is associated with downregulation of p-glycoprotein, resulting in potentiation of cytotoxic cancer chemotherapy in a number of cell types [66–68]. This potential effect of tamoxifen was tested in several phase I to III trials with mixed results failing to establish such benefit; nonetheless, results from these trials showed that even high-dose tamoxifen has little effect on the toxicities and pharmacokinetics of standard cancer chemotherapy (Table 1). Interestingly, p-glycoprotein is also expressed in the wall of ovarian capillaries [69] and is responsible for detoxification and steroid transport. Thus, TAM may inhibit chemotherapy transport into the ovary by altering levels of p-glycoproteins.

TABLE 1.

Studies of concurrent TAM and other cancer treatments.a

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a 

AEBS, antiestrogen binding site; ADR, adriamycin; DAN, daunorubicin; CAF, cyclophosphamide + doxorubicin + 5-fluorouracil; CDB, cisplatin + dacarbazine + carmustine; CDDP, cisplatin; CEF, cyclophosphamide + epirubicin + 5-fluorouracil; CFP, cyclophosphamide + 5-fluorouracil + prednisone; CHOP, cyclophosphamide + doxorubicin + vincristine + prednisone; CHOPE, cyclophosphamide + doxorubicin + vincristine + prednisone + etoposide; CIS, cisplatin; CMF, cyclophosphamide + methotrexate + 5-fluorouracil; CMFP, CMF + prednisone; CMFV, CMF + vincristine; CTX, cytoxan (cyclophosphamide); EPN, epirubicin; ER, estrogen receptor; 5FU, 5-fluorouracil; IFNβ, interferon β; ISG, IFN-stimulated gene expression; L-PAM, L-phenylalanine mustard; MFL, methotrexate + 5-fluorouracil + leucovorin; MTX, methotrexate; N/A, not applicable; ND, not discussed; PGP, p-glycoprotein; PK, pharmacokinetic, Rad, radiotherapy; TAM, tamoxifen or 4-hydroxytamoxifen (in vitro); TES, tesmilifene; TOR, toremifene; Vin, vinblastine; +, increased; = , no effect; −, decreased.

The Safety of Concurrent Use of TAM with Chemotherapy for Fertility Preservation

Nearly all current use of TAM is for the treatment and prevention of ER-positive (luminal A/B) breast cancer. Treatment protocols can include TAM monotherapy or, more commonly, cytotoxic chemotherapy combinations, such as Cy, methotrexate, and 5-fluorouracil, followed by TAM. Secondary prevention with TAM to prevent recurrence of cancer cells in women who have already undergone treatment for breast cancer after treatment for up to 10 yr is now standard care. More than 12 human trials have examined the impact of concurrently administered TAM and chemotherapy on breast cancer treatment outcomes, including five phase III studies (Table 1). Three of these found no significant impact of concurrent TAM on cancer treatment [70–72]. Mouridsen and colleagues found improved treatment outcomes with concurrent TAM [73]. In the relevant National Surgical Adjuvant Breast and Bowel Project trial, concurrent use of TAM with melphalan and 5-fluorouracil had little impact on most patients. However, worse outcomes were found in the subset of patients with ER-negative/progesterone-negative disease [74]. Two smaller trials comparing sequential versus concurrent TAM and radiation therapy for breast cancer found no difference in clinical outcome between groups [75, 76].

The concurrent use of TAM with combination chemotherapy in breast cancer patients is probably the most demanding (and the most common) clinical scenario for fertility preservation with TAM. The theoretical concern here is that cytostatic actions of TAM on breast tissue will render at least ER-positive breast cancers less sensitive to cytotoxic chemotherapy. As described above, clinical trials do not appear to bear this out and recent trials continue to explore concurrent TAM and chemotherapy as breast cancer therapy [70]. One exception may be hormone receptor-negative breast cancer. The definitive National Surgical Adjuvant Breast and Bowel Project trial did find worse outcomes when TAM was given concurrently with chemotherapy in premenopausal hormone receptor-negative disease [77]. Osborne and colleagues made similar observations in vitro [78]. Interpretation of any fertility data from such trials is further confused by the fact that the majority of patients in these trials were postmenopausal, reflecting the typical patient population for the breast cancer but not the population seeking fertility preservation. Additionally, patients routinely continue to receive TAM for 5 (and now 10) yr after treatment [79], resulting in reversible iatrogenic amenorrhea.

In addition to breast cancer, tamoxifen was shown to improve cancer therapy in vitro in lymphoma and leukemia cell lines by downregulating p-glycoprotein [80]. This led to several human clinical trials in lymphoma and leukemia patients culminating in a phase III trial examining the effect of Cy, hydroxydaunorubicin, oncovin, and prednisone alone or in combination with high-dose TAM [81–84]. These trials found similar outcomes regardless of TAM addition.

Other SERM Candidates for Ovarian Protection During Cancer Treatment

To our knowledge, TAM is the only SERM that has been tested and shown to protect the ovary from cancer treatments. Raloxifene, another SERM, has also been used for ovarian stimulation protocols in assisted reproductive technology and offers similar effects in promoting follicular growth as TAM [85]. In addition, an alternative SERM, tesmilifene, has been tested extensively as a potentiator of chemotherapy action in a number of resistant cancer types [86–88]. In early clinical trials, tesmilifene was shown to increase cytotoxic effects of anthrocyclines (i.e., DOX) [89]. Similar to TAM, tesmilifene enhances cytotoxicity of chemotherapy drugs by selectively targeting p-glycoprotein [90]. Raloxifene and tesmilifene seem to exert TAM-like actions in the ovary and during cancer treatment; however, their potential as an ovarian protectant against chemotherapy has yet to be tested.

SUMMARY

In retrospect, it is not surprising that TAM has selective effects on the ovary. These effects appear to be directly protective to the smallest classes of ovarian follicles—the majority of the follicular reserve. Estrogen receptors, and particularly ERβ, are plentiful in the ovary [91, 92], and protective actions of TAM have been observed for a number of other tissues. The differential expression of ERs, in addition to differences in ER cofactors and local concentrations of other ER ligands, may underlie the apparent ability of TAM to protect ovarian tissue while permitting cancer treatment. While a number of human trials have already tested treatment and survival endpoints when TAM is combined with other antineoplastics or radiation treatment—predominantly with little effect—caution is needed because these populations were mostly postmenopausal and at least one trial found a negative impact of TAM on outcomes for hormone receptor-negative disease. The potential use of TAM for fertility preservation in other tumor types appears more immediately feasible.

TAM is a drug with over 20 million patient-years of use in female cancer patients [93], giving strong safety data in comparison to other medical countermeasures used for fertility preservation. It has been shown preclinically to protect the ovary from a number of follicular toxicants, including cancer treatment drugs cyclophosphamide and doxorubicin as well as therapeutic radiation. Nevertheless, a number of important questions remain unanswered: 1) the mechanism of TAM action during fertility preservation and how this compares with tumoricidal actions in humans have not been established, 2) the necessity of concurrent administration of TAM (vs. pre- or posttreatment) for ovarian protection has not been tested, 3) the effect of other SERMs and aromatase inhibitors are unknown, and 4) the safety of concurrent TAM and chemotherapy administration in breast cancer patients, particularly those with ER-negative disease, remains a question. However, TAM does offer the promise of a convenient, inexpensive, and widely used cancer treatment that can be translated for fertility preservation in some clinical settings, particularly for cancers where TAM may be a potentiator of cancer treatment.

FIG. 2.

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A) Mature rat oocytes exposed to vehicle (CONT), 4-hydroxytamoxifen (4HT), doxorubicin (DOX), or DOX+4HT for 26 h. Healthy oocytes surrounded by zona pellucida were observed after CONT and 4HT treatment. DOX induces fragmentation in cultured oocytes, an effect that is antagonized by the addition of 4HT. Original magnification ×400. B) Percentage of oocytes undergoing fragmentation. Oocytes incubated with DOX showed increased fragmentation rate compared with CONT. This elevated fragmentation rate was inhibited by the addition of 4HT. The total number of oocytes cultured in each treatment group is indicated in parentheses inside the respective bar. The asterisk (*) indicates a significant difference in comparison to CONT. Adapted from Ting and Petroff (2010) [1] with permission.

ACKNOWLEDGMENT

The authors would like to thank Dr. John Risinger for critical reading of this manuscript and the Journal of Assisted Reproduction and Genetics for use of figures.

Footnotes

1

Support was provided by the NIH Center for Biomedical Research Excellence at the University of Kansas Medical Center.

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