INTRODUCTION — Several toxins can cause primary hypogonadism. Some are lifesaving therapies, such as anticancer drugs and radiation therapy. Others include cigarette smoke, viruses, and radioactivity (see "Pathogenesis and causes of spontaneous primary ovarian insufficiency (premature ovarian failure)", section on 'Ovarian toxins'). Anticancer drugs and radiation therapy are the most common of the known ovarian toxins. It is estimated that up to 1 in 1000 persons under age 20 years will have been cured of cancer by these treatments by the year 2000, and many of them will have forgotten their treatment by the time they seek care for reproductive dysfunction. As an example, in a survey of 1928 adult survivors of childhood cancer, 14 percent denied having had cancer and 18 percent misclassified their treatment [1]. Ovarian failure due to anticancer drugs and radiation will be reviewed here. Other causes of premature ovarian failure, an overview of fertility in cancer survivors, and options for fertility preservation in patients undergoing gonadotoxic therapy are discussed elsewhere. (See "Pathogenesis and causes of spontaneous primary ovarian insufficiency (premature ovarian failure)" and "Overview of infertility and pregnancy outcome in cancer survivors" and "Fertility and reproductive hormone preservation: Overview of care prior to gonadotoxic therapy or surgery".)
CHEMOTHERAPEUTIC DRUGS
Ovarian effects — Most anticancer drugs affect dividing cells and, therefore, would be expected to affect the granulosa and theca cells of the ovary more than the nondividing oocytes. However, the effect of these drugs on ovarian function varies widely, some having no effect and others causing permanent hypogonadism (table 1). Typically, the ovaries of women who received chemotherapy have normal to mildly decreased numbers of primordial follicles and a greater decrease in the numbers of larger maturing follicles [2,3], indicating a greater effect on follicular development than on oocytes.
Consistent with these histology findings are the clinical observations that many women, especially under 40 years of age, develop amenorrhea during chemotherapy, often with high serum gonadotropin concentrations, but menstrual function and, in some cases, fertility may return several months to years after the cessation of therapy [4-6].
Individual agents — Alkylating drugs, such as cyclophosphamide, are the best documented and most potent at inducing ovarian failure [7]. They alter base pairs, leading to DNA cross-links, and introduce single-strand DNA breaks [8]. As a result, they can theoretically affect both resting cells, such as oocytes, and dividing cells. The effects are age, dose, and drug dependent. Younger women are affected less often than older women, presumably because they have more remaining oocytes. In one study, as an example, all women over age 40 years had amenorrhea after receiving more than 5.2 g of cyclophosphamide, whereas the dose required to cause amenorrhea in younger women was 9.5 g [9].
Variable susceptibility to ovarian dysfunction — However, there is considerable variation in susceptibility, with some women having normal ovarian function but others of the same age having permanent primary hypogonadism after high doses of a single drug. (See "Acute side effects of adjuvant chemotherapy for early-stage breast cancer" and "Overview of long-term complications of therapy in breast cancer survivors and patterns of relapse" and "General toxicity of cyclophosphamide in rheumatic diseases".)
Biochemical markers of ovarian reserve — Anti-müllerian hormone ([AMH] also known as müllerian inhibiting substance [MIS]) is a biochemical marker of ovarian reserve (in addition to inhibin and follicle-stimulating hormone [FSH]). Serum concentrations of AMH decline rapidly during chemotherapy and may be useful for evaluating the ovarian toxicity of chemotherapy regimens [10-12]. However, its clinical use is not well established. (See "Evaluation of female infertility", section on 'Anti-müllerian hormone'.)
Multiple drug regimens — Most women with cancer are treated with multiple drugs, so it is easier to evaluate the consequences of specific treatments rather than single drugs. In addition, standard treatment regimens changed over time. For example, MOPP (mechlorethamine, vincristine, procarbazine, and prednisone), an early standard regimen used for Hodgkin lymphoma, induced permanent primary hypogonadism in 12 to 46 percent of women treated, and the onset of amenorrhea was more rapid and its incidence was higher in those over age 24 years [2,13,14]. The wide range of primary hypogonadism is related, in part, to different definitions and duration of amenorrhea used in individual studies. (See "Acute side effects of adjuvant chemotherapy for early-stage breast cancer", section on 'Chemotherapy-induced amenorrhea'.)
Currently used regimens for Hodgkin lymphoma have variable reproductive toxicities. The combination of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) is the preferred therapy for most Hodgkin lymphoma patients, and it is associated with a low incidence of chemotherapy-induced ovarian failure. In contrast, with BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) or escalated BEACOPP, approximately 50 percent of women develop ovarian failure that is not prevented by use of oral contraceptives or gonadotropin-releasing hormone (GnRH) analogues. (See "Initial treatment of advanced (stage III-IV) classic Hodgkin lymphoma".)
In women with early-stage breast cancer, two commonly used adjuvant chemotherapy regimens are cyclophosphamide, methotrexate, and fluorouracil (CMF), and anthracycline-based regimens, such as doxorubicin plus cyclophosphamide (AC). In one study, the risk of ovarian failure appeared to be greater with CMF when compared with AC regimens [15]. The risk of ovarian failure with different adjuvant chemotherapy regimens for early breast cancer is reviewed in detail elsewhere. (See "Acute side effects of adjuvant chemotherapy for early-stage breast cancer", section on 'Chemotherapy-induced amenorrhea'.)
The results in girls and young women treated with regimens specific for leukemia and solid tumors are different. In a study of 35 pre- and postpubertal girls with leukemia who received various treatments, only three had primary hypogonadism a mean of 49 months after treatment [4]; one had many residual follicles on ovarian biopsy and the other two resumed menses 8 and 14 months later, suggesting they had a disorder of granulosa cell responsiveness rather than oocyte depletion. Girls with acute lymphoblastic leukemia treated with cyclophosphamide, cytarabine (ara-C), and other drugs and cranial irradiation have a slightly early onset of puberty but high serum FSH and low inhibin concentrations, again suggestive of granulosa and thecal cell damage [16].
Although it would be ideal to modify chemotherapy regimens to minimize the negative effect on ovarian function, the primary focus of chemotherapy treatment in these situations is to maximize the probability of cure. The primary approaches to dealing with the ovarian complications of chemotherapy have included suppression of ovarian function and alternative fertility options, as discussed below. (See 'Fertility preservation' below and "Fertility and reproductive hormone preservation: Overview of care prior to gonadotoxic therapy or surgery".)
RADIATION THERAPY — Radiation therapy is more damaging to ovarian tissue than chemotherapy. Its effects also are dose- and age-dependent, but unlike chemotherapy, radiation is particularly toxic to oocytes [17]. In younger women, radiation can cause transient amenorrhea that resolves after 6 to 18 months, presumably after recruitment and development of a new cohort of primary follicles. Such a response has also been documented in women receiving radioactive iodine therapy for thyroid cancer, in whom approximately 30 percent had reversible primary hypogonadism [18]. (See "Differentiated thyroid cancer: Radioiodine treatment", section on 'Gonadal function and fertility'.)
Although doses of more than 600 rads (6 Gy) consistently cause permanent primary hypogonadism in women over age 40 years [19], the impact of lower doses varies, with reports of conceptions in women under 20 years of age who received up to 3000 rads (30 Gy) [20-22]. Treatment of women with Hodgkin lymphoma with pelvic irradiation in addition to chemotherapy increased the risk of ovarian failure from 0 to 68 percent in one study [13].
One study estimated the radiosensitivity of the oocyte to be <2 Gy [23]. Based upon this estimate, the authors calculated the dose of radiotherapy that would result in immediate and permanent ovarian failure in 97.5 percent of patients as follows [24]:
●20.3 Gy at birth
●18.4 Gy at age 10 years
●16.5 Gy at age 20 years
●14.3 Gy at age 30 years
Although these estimates have not been confirmed in other studies, they may be useful for counseling patients and families prior to initiating radiation therapy.
It is important to note that most young women who are going to receive pelvic radiation therapy typically have an attempt to move the ovaries outside the field of radiation. (See 'Oophoropexy' below.)
There is no evidence for an increased rate of congenital anomalies in the offspring of women treated with chemotherapy, radiation therapy, or both [25]. There may, however, be an increase in the rate of early pregnancy loss [17], and small for gestational age infants [26], and an increased risk of malformations in fetuses exposed to radiation in utero. (See "Overview of infertility and pregnancy outcome in cancer survivors".)
CHILDHOOD CANCER SURVIVORS — Ovarian failure occurs in a significant percentage of childhood cancer survivors. In a report from the Childhood Cancer Survivor Study (CCSS) of 2819 survivors of childhood cancer over age 18 years and a control group of 1065 female siblings of participants in the CCSS, the cumulative incidence of premature ovarian failure in the survivor group was 8 percent compared with 0.8 percent in the siblings [27]. One study estimates the rate at 10.9 percent [28].
Significant risk factors for nonsurgical premature menopause included older age at diagnosis, exposure to increasing doses of radiation to the ovaries (≥1000 cGy ovarian irradiation), increasing alkylating agent score (based on number of alkylating agents and cumulative dose), and a diagnosis of Hodgkin lymphoma. The cumulative incidence of nonsurgical premature menopause was approximately 30 percent in survivors who had been treated with both alkylating agents and abdominopelvic radiation. (See "Endocrinopathies in cancer survivors and others exposed to cytotoxic therapies during childhood", section on 'Ovarian dysfunction'.)
FERTILITY PRESERVATION — Options for the preservation of fertility in women undergoing cytotoxic therapy are reviewed briefly here and discussed in detail elsewhere. (See "Fertility and reproductive hormone preservation: Overview of care prior to gonadotoxic therapy or surgery".)
Prevention of ovarian failure
Ovarian suppression — Ovarian toxicity from chemotherapy may be reduced by diminishing ovarian function during the period of treatment. This can be reversibly achieved by the administration of gonadotropin-releasing hormone (GnRH) agonists or oral contraceptives. In animals, GnRH agonists reduce the risk of chemotherapy-induced ovarian damage. The evidence in humans of a benefit from such an approach has been limited. Systematic reviews and meta-analyses of randomized trials suggest that addition of a GnRH agonist may be beneficial for protection of menstrual function, but there is no evidence to date that GnRH agonist co-treatment improves the rate of spontaneous pregnancy after chemotherapy. Other trials may determine the fertility outcome. (See "Fertility and reproductive hormone preservation: Overview of care prior to gonadotoxic therapy or surgery".)
Oophoropexy — Transposing the ovaries out of the radiation field is an option for preserving gonadal function in patients receiving pelvic radiation without chemotherapy. However, success rates with this procedure are inconsistent. (See "Fertility and reproductive hormone preservation: Overview of care prior to gonadotoxic therapy or surgery" and "Ovarian transposition before pelvic radiation".)
Cryopreservation techniques
Embryos — Embryo cryopreservation is a well-established technique for storing surplus embryos of patients undergoing in vitro fertilization (IVF) procedures. With current freezing techniques, the implantation potential of frozen-thawed embryos approaches that of fresh embryos. However, cryopreservation of embryos may not personally or be technically feasible for every patient. (See "Fertility and reproductive hormone preservation: Overview of care prior to gonadotoxic therapy or surgery".)
Oocytes — Cryopreservation of oocytes is an option for women without partners who do not opt to use donor sperm for IVF. In contrast to cryopreservation of embryos and sperm, oocyte cryopreservation is technically more challenging since oocytes are more sensitive to cryoinjury. Oocyte cryopreservation is no longer considered experimental by the American College of Obstetrics and Gynecology [29]. (See "Fertility and reproductive hormone preservation: Overview of care prior to gonadotoxic therapy or surgery".)
Ovarian tissue — Another experimental prevention strategy is to obtain ovarian tissue for cryopreservation that can later be implanted. The potential advantages of this approach are that the tissue can be obtained without the need for ovarian stimulation. (See "Fertility and reproductive hormone preservation: Overview of care prior to gonadotoxic therapy or surgery", section on 'Fertility preservation'.)
Ovarian tissue cryopreservation is still considered investigational, and it is recommended that patients undergo a research protocol when seeking this treatment [30]. Other fertility options for women with ovarian failure are discussed elsewhere. (See "Treatments for female infertility".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Primary ovarian insufficiency".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Premature menopause (primary ovarian insufficiency) (The Basics)")
●Beyond the Basics topics (see "Patient education: Primary ovarian insufficiency (Beyond the Basics)")
SUMMARY
●Women undergoing chemotherapy can develop amenorrhea, which may be temporary or result in premature or early menopause.
●Chemotherapy effects on the ovary are age, dose, and drug dependent, with alkylating agents the most potent. (See 'Chemotherapeutic drugs' above.)
●Radiation therapy, which is also age and dose dependent, is toxic to the oocytes, with permanent ovarian failure estimated at 97.5 percent of women with 18.4 Gy at age 10 years and 14.3 Gy at age 30 years.
(See 'Radiation therapy' above.)
●The rate of primary ovarian insufficiency (POI) in childhood cancer survivors is 8 to 10.9 percent. (See 'Childhood cancer survivors' above.)
●Oophoropexy should be used to remove the ovaries from the radiation field, and embryo or oocyte cryopreservation can be used before treatment if feasible. The effects of other potential fertility preservation treatments, such as gonadotropin-releasing hormone (GnRH) agonists and or ovarian cryopreservation, are still considered investigational. (See 'Fertility preservation' above.)
