| | Preserving reproductive function in women with cancerCancer treatment often ends a woman’s ability to conceive, but a number of new techniques to preserve reproductive function— hormonal manipulation, cryopreservation of embryos or ovarian tissue, and conservative surgery for early gyn cancers—offer an increased measure of hope.
As more young patients with early malignancies are being cured, increased emphasis is being placed on optimizing their quality of life and preserving reproductive function. A number of innovative approaches are now available to minimize the negative impact of cancer treatment on reproductive function—including hormonal manipulation, cryopreservation of embryos or ovarian tissue, and alternatives to definitive surgery for malignancy.
The effects of radiation on reproductive function  The effects of radiation on female reproductive function are both age- and dose-dependent.1 Studies indicate that a total dose of less than 60 cGy (rads) delivered to the pelvis is considered unlikely to cause infertility, while a total dose in excess of 800 rads is sufficient to cause permanent infertility secondary to ovarian failure.2 To put this in perspective, the total dose of pelvic radiation required as primary treatment for cervical cancer is 8,500 rads. When pelvic radiation is offered in an adjuvant setting after primary surgery for cervical or endometrial cancer, the total dose often exceeds 4,500 rads. Therefore, radiotherapy to the pelvis as primary or adjuvant treatment will induce ovarian failure in virtually all women who still have their adnexae at the time they are treated for these malignancies. Ionizing radiation interacts with intracellular water to create highly reactive free radicals that interfere with a cell’s ability to reproduce.1, 2, 3, 4, 5, 6 We have learned about the effects of ionizing radiation in women from several historical sources:
•Young women with Hodgkin’s disease were routinely treated with up to 3,500 rads to the pelvis, which uniformly resulted in amenorrhea and infertility.7
•Pelvic radiation was once administered as treatment for menorrhagia.6 While this strategy effectively controlled the condition, the majority of women who received radiotherapy likely became menopausal. Of those who did become pregnant after treatment, most pregnancies ended in spontaneous abortion, probably due to chromosomal abnormalities or adverse effects on the endometrium interfering with implantation.
•Radiotherapy to the pituitary and pelvis was once prescribed as treatment for infertility.5 The dose of radiation to the pituitary and pelvis was significantly less than in the menorrhagia study, and as a result 39% of women were able to conceive. It became apparent that there had to be a threshold dose of radiation to the ovaries below which ablation of reproductive function did not occur.
Transposition of the ovaries To minimize radiation exposure and the risk of ovarian failure, surgical transposition of ovaries out of the pelvis has been recommended prior to adjuvant pelvic radiotherapy.8, 9 The ovaries can be transposed high in the paracolic gutter above the pelvic brim, just beneath the lower pole of the kidney.10 The procedure can be done laparoscopically or at the time of laparotomy for malignancies in which adjuvant pelvic radiotherapy is anticipated.10, 11, 12, 13, 14, 15, 16, 17 Despite its technical feasibility, ovarian transposition does not necessarily protect ovarian function following pelvic radiotherapy.18–21Table 1 summarizes the rates of ovarian failure after adjuvant radiotherapy following radical hysterectomy and ovarian transposition for cervical cancer. In general, the mean age at which menopause occurs after radical hysterectomy, ovarian transposition, and pelvic radiotherapy appears to be at least a decade earlier than that expected in the general population. As devascularization injury to the ovary with hysterectomy results in menopause approximately five years before expected in the general population,22 it is possible that exposure to pelvic radiation after this initial devascularization may be sufficient to induce ovarian failure in the majority of women undergoing the procedure. Also, the rate of symptomatic ovarian cysts requiring medical or surgical intervention (oophorectomy) following transposition is significant—as high as 25%.2021 | | |  | Criteria | Feeney18 | Buekers19 | Chambers21 | Anderson20 | |
|---|
| Mean age at surgery (in years) | 33.5 | 32.6 | NR | 31 | |
| N (without pelvic radiation) | 104 | 61 | 24 | 58 | |
| Ovarian failure (without radiation) | 3 (2.9%) | 1 (2%) | 1 (4%) | 9 (16%) | |
| Mean age of menopause (without radiation), in years | NR | 47.2 | NR | 40 | |
| N (with pelvic radiation) | 28 | 17 | 14 | 24 | |
| Ovarian failure (with pelvic radiation) | 14 (50%) at 24 months | 10 (59%) at 12 months | 4 (29%) at 35 months | 20 (83%) at 13 months | |
| Mean age of menopause (with radiation), in years | NR | 36.6 | 38.5 | 33 | | | | |
Key points
■The effects of radiation and chemotherapy on reproductive function are generally age- and dose-dependent.
■Surgical transposition of ovaries out of the pelvis may not mitigate the effects of pelvic radiation on ovarian function.
■Gonadotropin-releasing hormone agonists may offer the most consistent pharmacologic method of preserving reproductive function.
■Cryopreservation of embryos is a limited option for women of reproductive age who are about to begin cancer treatment with chemotherapy and/or radiation.
■There is increasing evidence that fertility-sparing treatment may be appropriate in select cases of cervical cancer (radical trachelectomy), endometrial cancer (high-dose progestins), and ovarian cancer (conservative surgery and chemotherapy).
Even if ovarian function is preserved after transposition and pelvic radiotherapy, it is unlikely that fertility can be preserved in those who still have a uterus. Radiotherapy can adversely affect local uterine vasculature with subsequent impairment of implantation if conception should occur.23 Surrogate pregnancy may be an available option for women undergoing radiotherapy who wish to use their own oocytes. The effects of chemotherapy on reproductive function As with radiation, the effects of chemotherapy on reproductive function are both age- and dose-dependent.24–25 Toxicities to ovarian function range widely, depending on the drug’s mechanism of action. Alkylating agents are among the more toxic as they result in DNA cross-links with single and doublestrand breaks that inhibit synthesis of DNA, RNA, and proteins.26 These drugs, such as cyclophosphamide, act in a cell cycle-nonspecific manner. Cyclophosphamide has an important role in current treatment protocols, especially for breast cancer.27 The dose of cyclophosphamide resulting in ovarian failure is age-dependent,28 with a cumulative dose of 20.4 g required to induce ovarian failure in a woman 20–29 years old, versus a cumulative dose of 5.2 g in a woman over 40. To put this in perspective, an average-size woman with a body surface area of 1.7 m2 receiving six cycles of CMF (cylophosphamide, methotrexate, 5-fluorouracil) or CEF (epirubicin replacing methotrexate) would receive a total dose of 11–15 g of cyclophosphamide chemotherapy.29 Therefore, most women treated with CMF or CEF are rendered menopausal at the completion of treatment.30–31 Certain chemotherapeutic drugs are known to be minimally toxic to ovarian function. These are the cell cycle-specific drugs such as anti-metabolites (methotrexate, 5FU), plant alkaloids (vincristine, vinblastine, etoposide), and antibiotics (actinomycin-D, doxorubicin, bleomycin).10 In contrast, these drugs are highly toxic to testicular function because of the constant cell division in spermatogenesis. The literature on the use of these drugs in treating women with gestational trophoblastic disease and ovarian germ cell tumors suggests that reproductive function is not impaired.32–40 Although cisplatin is an alkylating-like agent, it has been incorporated into chemotherapy protocols for ovarian germ cell tumors without significant impact on ovarian function.34,38 Hormonal manipulation It is well recognized that the ovary of a prepubertal girl has a higher threshold to radiation and chemotherapy than the ovary of a woman of reproductive age.2,28,41 This is related to the fact that there is no meiotic activity and a higher number of oocytes in the prepubertal ovary. Hormonal manipulation to suppress ovulation has been proposed as a method of “saving” oocytes, rendering the ovary quiescent as in its prepubertal state. This is one method of preventing ovarian failure from cancer treatment. Use of oral contraceptives Ovarian suppression during chemotherapy using oral contraceptives has produced variable outcomes. One such study involved six women between the ages of 18 and 32 who had used oral contraceptives during MVPP chemotherapy (nitrogen mustard, vinblastine, procarbazine, and prednisone) for Hodgkin’s disease.42 Five of the six resumed normal menses following treatment, and one eventually conceived. Ovarian biopsies revealed preservation of follicles in women who used oral contraceptives during chemotherapy, in contrast to historical controls who did not use oral contraceptives. A different outcome was reported in a cohort of 44 women aged 13 to 45 (median age 23) who also received MVPP chemotherapy for Hodgkin’s disease.43 Only two of the nine women who took oral contraceptives throughout chemotherapy resumed normal menses following treatment. The remaining seven had amenorrhea or oligomenorrhea after treatment, and all experienced hot flushes in keeping with premature ovarian failure after discontinuing oral contraceptives. However, some of these women had received radiation in addition to chemotherapy, and this may have been a confounding factor. Gonadotropin-releasing hormone agonists More consistent results have been reported with the use of gonadotropin-releasing hormone (GnRH) agonists. In one study, a cohort of 44 women, aged 15 to 40, received monthly depot injections of a GnRH agonist prior to starting chemotherapy for lymphoma, leukemia, or autoimmune diseases, for a maximum of six months.44 A control group of 55 women received similar chemotherapy without a GnRH agonist. All but one of the women in the GnRH group resumed spontaneous ovulation and menses within six months of completing treatment, compared with only 40% of the controls. Unfortunately, the ages of the women in the control group were not reported. Similar results come from a study of five women aged 14 to 20.45 They received monthly intramuscular injections of a GnRH agonist (leuprolide acetate 3.75 mg) soon after starting multiagent chemotherapy prior to bone marrow transplantation for Hodgkin’s disease or acute myeloblastic leukemia. All five treated with leuprolide resumed menses 45 to 120 days after completing chemotherapy. A second treatment group of seven women, aged 14 to 18, received high-dose chemotherapy and radiation for Hodgkin’s disease, followed by monthly intramuscular injections of a GnRH agonist for a maximum of six months. Five of the seven women resumed normal menses. By comparison, four controls between the ages of 17 and 20 all developed secondary amenorrhea and required long-term hormone replacement therapy. A second control group included five girls between the ages of 3 and 7.5 who received multiagent chemotherapy. These patients were followed for 18 years, and all had spontaneous menarche between the ages of 12 and 17.9. Although we cannot draw a definitive conclusion from this study, it appears that prepubertal girls may be spared the potential deleterious effects of chemotherapy because of the endocrine “quiescence” of their ovaries during treatment. During treatment with a GnRH agonist, initial stimulation is followed by suppression of gonadotropin release; decreased secretion of estrogens, progestogens, and androgens; and finally cellular apoptosis and follicular atresia.46 As a result, oocyte maturation is inhibited and involution occurs, thereby avoiding the deleterious effects of chemotherapy on the dividing cell.47 In contrast to oral contraceptives, GnRH agonists revert the ovary to its prepubertal state, which may explain its effectiveness in protecting ovarian function. Cryopreservation of embryos or ovarian tissue Preservation of reproductive function may be achieved by cryopreservation of embryos, or more recently, cryopreservation of ovarian tissue with subsequent grafting as a xenotransplant or autotransplant. Embryo cryopreservation is highly successful and can be considered prior to radiation or chemotherapy. However, there are a number of disadvantages of embryo cryopreservation, including:
•expense (the cost of fertility drugs, investigations, and technical services can run as high as $10,000 per cycle);48
•the risk of ovarian hyperstimulation syndrome, which is potentially life-threatening;49
•the need for hormones that may be contraindicated in certain malignancies (e.g., breast cancer);
•delay in initiating definitive treatment with chemotherapy or radiation in order to facilitate the entire process of embryo cryopreservation; and
•the fact that this method is impossible for young women who do not have a partner and are unwilling to use donor sperm.
While cryopreservation of sperm is well-documented and is the optimal method of preserving reproductive potential in men, cryopreservation of oocytes is not yet an option for young women. Oocytes are much more sensitive than sperm to the freeze-thaw process.50 However, cryopreservation of primordial follicles, either alone or in strips of ovarian cortical tissue, has been much more promising.51 Ovarian tissue cryopreservation is an emerging technique that has recently attracted significant media attention.52–53 The ovarian tissue can be grafted as a xenograft to another host, such as an immunodeficient SCID mouse.54–55 Successful grafts have occurred on the renal capsule of the SCID mouse, presumably because the rich blood supply of the capsule enhances the viability of the graft, rendering it less likely to be rejected.56 However, xenotransplantation carries the unresolved ethical dilemma of animal-to-human tissue transfer, and the possibility of transfer of unknown infectious agents from animal to human. More recently, autotransplantation of cryopreserved ovarian tissue has been explored. Cryopreserved ovarian tissue can be grafted to a heterotopic site such as subcutaneous tissue in the abdomen.57–58 Alternatively, cryopreserved ovarian tissue can be transplanted back to the original ovarian pedicle, an orthotopic site. This technique of orthotopic autotransplantation appears to re-establish blood supply to the autotransplanted tissue.53 Subsequently, a recent article in The Lancet described a 32-year-old woman who delivered a healthy term infant seven years after cryopreservation of ovarian tissue prior to multiagent chemotherapy for Hodgkin’s disease. After she had completed treatment, she underwent orthotopic transplantation of her ovarian tissue, and she conceived 11 months after transplantation. This represents the first case report of a live human birth following autotransplantation of cryopreserved ovarian tissue after treatment for cancer.59 Many legal and ethical issues surrounding need to be resolved. An unknown risk is the possibility of undetected microscopic tumor cells in cryopreserved ovarian tissue, and the subsequent reintroduction of tumor cells after transplantation of this tissue following completion of cancer treatment. Furthermore, as the technique of ovarian cryopreservation is refined and ovarian tissue banking becomes a reality, a decision will need to be made about the application of this technology. Will it be reserved for cancer patients alone, or will there be a role for cryopreservation in women who wish to delay their childbearing for reasons relating to personal or career circumstances? Obviously, additional experience with autotransplantation of cryopreserved ovarian tissue is required before this technique can be introduced universally into clinical practice. Conservative management of gyn malignancies Ovarian, cervical, and endometrial cancer typically require treatment involving extirpative surgery, radiation, and/or chemotherapy, all of which eliminate reproductive potential. Over the last few decades, there has been an evolution in the treatment of early-stage gynecologic malignancies, as well as advanced ovarian germ cell tumors. Early cervical cancer: trachelectomy The standard treatment for women with earlystage cervical cancer (excluding microinvasive cancer) remains radical hysterectomy with pelvic lymphadenectomy or radical radiotherapy.60 However, both treatments are less than desirable in the young woman with an early cervical cancer who wishes to preserve her fertility. Within the past decade, radical trachelectomy has been proposed as a fertility-sparing treatment for a select group of women with early-stage cervical cancer for whom a radical hysterectomy with pelvic lymphadenectomy would usually be recommended.61–67 Cervical cancer tends to spread laterally into the parametria, inferiorly to the upper vagina, and very rarely spreads superiorly into the uterus.68 Thus in theory, without compromising survival, the cervix and surrounding parametria can be resected from the lower uterine segment (i.e., trachelectomy), leaving the rest of the uterus intact to allow for pregnancy. A summary of studies describing radical trachelectomy and pelvic lymphadenectomy is presented in Table 2. The pelvic lymphadenectomy is usually carried out first (laparoscopically) to confirm the absence of metastatic nodes. | | | | Author | No. of patients | Median follow-up (months) | Recurrences | No. of women conceiving/No. attempting to conceive (No. of live births) | |
|---|
| Shepherd67 | 30 | NR | 0 | 8/13 (9) | |
| Dargent65 | 47 | 52 | 2 | 13/16 (10) | |
| Roy and Plante63 | 30 | 25 | 1 | 6/6 (4) | |
| Covens64 | 32 | 29 | 1 | 4/13 (3) | |
| Rodriguez66 | 3 | NR | 0 | 1/3 (1) | |
| Burnett84 | 21 | 31.5 | 0 | 3/3 (1) | |
| Schlaerth85 | 12 | 47.6 (mean) | 0 | 4/4 (2) | | | | |
Radical trachelectomy can be completed vaginally or abdominally. After the cervix and parametria have been removed, a permanent cerclage is placed at the lower uterine segment to prevent subsequent early pregnancy loss. While the cerclage does not necessarily require reproductive technologies to conceive, it does mandate Cesarean section for delivery. Overall, the recurrence-free survival after trachelectomy is comparable to that after standard radical hysterectomy.63–65, 67 While the benefits of trachelectomy are obvious— preservation of fertility and a reduced hospital stay, with rates of blood loss, complications, and recurrence-free survival similar to standard radical hysterectomy—only a very specific group of women with early cervical cancers will be eligible for this procedure. A tumor width of 2 cm has been suggested as a threshold size for eligibility.62,65,67 The presence of lymphovascular space invasion or the diagnosis of adenocarcinoma is not necessarily a contraindication to this procedure.69 A cone biopsy with pelvic lymphadenectomy may seem like another reasonable alternative to radical surgery or radiotherapy for early invasive cervical cancer. However, in one reported series there was discontinuous spread of tumor in three of four cases of extracervical disease.69 Simple conization may miss tumor emboli in the parametria or lateral portion of the cervix and thus does not appear to be an appropriate treatment for cervical cancer except for microinvasive carcinoma.70 Endometrial cancer: progestin therapy The conventional treatment for endometrial cancer is total abdominal hysterectomy and bilateral salpingo-oophorectomy. Endometrial cancer is uncommon in premenopausal women, and therefore preservation of fertility is rarely an important issue. Young women with obesity, non-insulin dependent diabetes, and polycystic ovaries are at increased risk for endometrial cancer because of chronic anovulation and prolonged exposure to endogenous estrogens unopposed by progesterone.70–74 The use of progestins as an alternative fertility-sparing method to treat endometrial cancer has been described in several series (Table 3). Complete responses to the progesteronecontaining intrauterine device have been described in one report.75 Most of the subjects in these studies had Grade 1 endometrioid carcinoma. There are only two case reports describing treatment of Grade 2 endometrial carcinoma with progestins.76–77 | | | | Author | No. of patients | Treatment | Response rate | Median follow-up (months) | No. of women conceiving/No. attempting to conceive (No. live births) | |
|---|
| Bokhman77 | 19 | 17 α-HPC, 500 mg × 3 months | 15/19 (79%) | NR | NR | |
| Kim79 | 21 | Various regimens, including MA 160 mg/d × 3 months | 13/21 (62%) | NR | 3/13 (6) | |
| Randall and Kurman80 | 12 | MA 40–160 mg/d × 2–18 months | 9/12 (75%) | 40 | 3/10 (5) | |
| Sardi86 | 4 | MPA 200–500 mg/d × 3–9 months | 3/4 (75%) | 35.7 | 2/4 (3) | |
| Duska87 | 12 | NR | 10/12 (83%) | 54 | 4/10 (5) | |
| Gottlieb88 | 13 | Various regimens, including MA 160 mg/d, MPA 200–600 mg/d, HPC 2–3 g/week, NA 5 mg/d | 13/13 (100%) | 78 | 5/3 (9) | |
| Jobo89 | 2 | MPA 600 mg/d × 22–29 weeks | 2/2 (100%) | 31, 60 | 2/2 (2) | |
| Pinto90 | 1 | MA 160 mg/d × 3 months | 1/1 (100%) | NR | 1/1 (1) | |
| Vinker91 | 1 | MPA 400 mg/d × 10 weeks | 0/1 (TAH, BSO, staging) | 48 | 0 | |
| Kaku92 | 12 | MPA 200–800 mg/d × 2–14 months | 9/12 (75%, but 2 recurred) | 24 | 2/2 (1) | |
| Imai93 | 15 | MPA × median 29 weeks | 8/15 (53%) | 59 | 2/2 (3) | |
| Wang94 | 9 | MA 160 mg/d +/− Tamoxifen 30 mg/d × 6 months | 8/9 (89%, but 2 recurred) | 69 | 3/2 (3, incl. twins) | |
| Ogawa95 | 1 | MPA 400 mg/d × 12 weeks | 1/1 (100%) | NR | 1/1 (1) | |
| Mitsushita96 | 1 | MPA 400 mg/d × 4 months, then 600 mg/d × 8 months | 0/1 (persistence, although conceived) | NR | 1/1 (1) | |
| Montz75 | 12 | Progesterone-IUD | 6/8 (75%) at 1 year | 12 | NR | | | | |
There is no consensus on the ideal progestational agent or dose to use for young women with endometrial cancer who wish to preserve their fertility. After a woman has responded to progestin therapy, it has been suggested that she continue to use low-dose progestins or oral contraceptives to prevent cancer recurrence until she is ready to attempt conception.78 Surveillance every three months with dilatation and curettage is recommended,79–80 with emphasis on the need for prompt, definitive surgical management with any evidence of recurrent cancer, and a recommendation for complete hysterectomy and bilateral salpingo-oophorectomy after childbearing has been completed. Ovarian cancer: conservative surgery Malignant ovarian germ cell tumors characteristically arise in children and adolescents. Conservative surgery is now the accepted standard of treatment; this includes a unilateral salpingo-oophorectomy and staging procedure.34–37,40 The uterus and contralateral ovary are left intact. Malignant germ cell tumors have a high rate of cure in spite of conservative surgery, and this relates to the biology of these tumors. First, germ cell tumors almost always present as a unilateral adnexal mass. The only exception is the dysgerminoma, with a rate of bilaterality of up to 15%.81 Second, recurrences of malignant germ cell tumors rarely develop in the uterus or contralateral ovary.24 Therefore, removing these structures at initial surgery would not have any impact on the risk of recurrent disease. Finally, malignant germ cell tumors are curable with multiagent chemotherapy, even in the setting of metastatic disease.40,82 For all these reasons, conservative surgery is feasible in malignant germ cell tumors without risk of compromise in survival. Epithelial ovarian cancer is rare in women of reproductive age. Conservative surgery for this cancer usually consists of unilateral salpingo-oophorectomy and staging for a select group of women under age 40 with Stage I ovarian cancer. The outcomes of conservative surgery for early-stage ovarian cancer are summarized in Table 4. These studies suggest that in a highly select group of young patients with earlystage ovarian cancer, conservative surgery may be considered.83 | | | | Author | No. of patients | No. of patients receiving adjuvant therapy | Recurrences | Median time to recurrence (months) | Median follow-up (months) | No. of women conceiving/No. attempting to conceive (No. of live births) | |
|---|
| Zanetta97 | 56 | 3 (platinum × 6) | 5/56 (9%) | 12 | 84 | 20/NR (17) | |
| Colombo98 | 56 | 16 (platinum) | 3/56 (5%) | 13 | 75 | 17/17 (16) | |
| Duska99 | 5 | NR | 0 | — | NR | 2/5 (2) | |
| Raspagliesi83 | 10 | 1 (radiation); 7 (chemotherapy) | 0 | — | 70 | 3/5 (2) | |
| Schilder100 | 52 (IA-42, IC 10) | IA-11 (PT, PC, M), IC-8 (PT, PC, M) | 5 (IA-4, IC-1) | 13 | 68 | 17/24 (26) | |
| Morice101 | 25 (IA-19, IC-1, II-2, unstaged-3) | IA1-1, IA2-4, greater than IA-4, chemotherapy and EBR in 1 | 7 (5 on remaining ovary) | 15 | 47 | 4/4 (3) | | | | |
Where do we go from here? Our current understanding of the reproductive sequelae of radiation and chemotherapy has enabled us to tailor cancer treatment to optimize fertility and hormonal preservation without compromising survival. While strategies such as ovarian transposition or suppressing ovarian function with oral contraceptives or GnRH agonists have been theoretically appealing, the rates of ovarian preservation are lower than originally expected, especially with surgical transposition. Research on ovarian tissue cryopreservation and transplantation is ongoing, and there are many ethical issues surrounding the use of such innovative technologies. We have come a long way in the treatment of gynecologic malignancies. In select women with early-stage cancers, we can offer fertility-sparing surgery without compromising patient survival. It is crucial to keep raising questions about the safety of all treatment strategies. It is most important to keep scrutinizing and evaluating outcomes while challenging existing dogma and practices. We must always remember that the primary principle of medicine, “primum non nocere,” must govern us as we proceed through this evolution in cancer care. See the complete listing of references for this article at www.srmjournal.org References 1.
1
Ash P
.
The influence of radiation on fertility in man
.
Br J Radiol
. 1980;271–278
.
2.
2
Damewood MD
, Grochow LB
.
Prospects for fertility after chemotherapy or radiation for neoplastic disease
.
Fertil Steril
. 1986;443–459
.
3.
3
Eifel PF
.
Radiation therapy
.
In:
Berek JS
, Backer NF
editor.
Practical Gynecologic Oncology
. Philadelphia: Lippincott Williams & Wilkins; 2000;p. 117–158
.
4.
4
Rowley MJ
, Leach DR
, Warner GA
, Heller CG
.
Effect of graded doses of ionizing radiation on the human testis
.
Radiat Res
. 1974;665–678
.
5.
5
Kaplan I
.
The treatment of female sterility with X-ray therapy directed to the pituitary and ovaries
.
Am J Obstet Gynecol
. 1958;447–453
.
6.
6
Dickson RJ
.
The late results of radium treatment for benign uterine haemorrhage
.
Br J Radiol
. 1969;582–594
.
7.
7
Hohl RJ
, Schilsky RL
.
Nonmalignant complications of therapy for Hodgkin’s disease
.
Hematol Oncol Clin North Am
. 1989;331–343
.
8.
8
Gradishar WJ
, Schilsky RL
.
Ovarian function following radiation and chemotherapy for cancer
.
Semin Oncol
. 1989;425–436
.
9.
9
Mendenhall NP
, Taylor BW
, Marcus RB
, Million RR
.
The impact of pelvic recurrence and elective pelvic irradiation on survival and treatment morbidity in early-stage Hodgkin’s disease
.
Int J Radiat Oncol Biol Phys
. 1991;1157–1165
.
10.
10
Clough KB
, Goffinet F
, Labib A
, et al.
Laparoscopic unilateral ovarian transposition prior to irradiation
(prospective study of 20 cases)
.
Cancer
. 1996;2638–2645
.
11.
11
Morice P
, Castaigne D
, Haie-Meder C
, et al.
Laparoscopic ovarian transposition for pelvic malignancies
(indications and functional outcomes)
.
Fertil Steril
. 1998;956–960
.
12.
12
Classe JM
, Mahe M
, Moreau P
, et al.
Ovarian transposition by laparoscopy before radiotherapy in the treatment of Hodgkin’s disease
.
Cancer
. 1998;1420–1424
.
13.
13
Tulandi T
, Al Took S
.
Laparoscopic ovarian suspension before irradiation
.
Fertil Steril
. 1998;381–383
.
14.
14
Howard FM
.
Laparoscopic lateral ovarian transposition before radiation treatment of Hodgkin disease
.
J Am Assoc Gynecol Laparosc
. 1997;601–604
.
15.
15
Treissman MJ
, Miller D
, McComb PF
.
Laparoscopic lateral ovarian transposition
.
Fertil Steril
. 1996;1229–1231
.
16.
16
Covens AL
, van der Putten HW
, Fyles AW
, et al.
Laparoscopic ovarian transposition
.
Eur J Gynaecol Oncol
. 1996;177–182
.
17.
17
Williams RS
, Littell RD
, Mendenhall NP
.
Laparoscopic oophoropexy and ovarian function in the treatment of Hodgkin disease
.
Cancer
. 1999;2138–2142
.
18.
18
Feeney DD
, Moore DH
, Look KY
, et al.
The fate of the ovaries after radical hysterectomy and ovarian transposition
.
Gynecol Oncol
. 1995;3–7
.
19.
19
Buekers TE
, Anderson B
, Sorosky JI
, Buller RE
.
Ovarian function after surgical treatment for cervical cancer
.
Gynecol Oncol
. 2001;85–88
.
20.
20
Anderson B
, LaPolla J
, Turner D
, et al.
Ovarian transposition in cervical cancer
.
Gynecol Oncol
. 1993;206–214
.
a Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Western Ontario, London, Ontario b Department of Obstetrics, Gynecology and Reproductive Sciences, University of Saskatchewan, Saskatoon, Saskatchewan  Division of Gynecologic Oncology, London Health Sciences Centre, 800 Commissioners Road East, London, Ontario, Canada N6A 4G5
PII: S1546-2501(04)00222-1 doi:10.1016/j.sram.2004.11.005 © 2004 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved. | |
|
FULL TEXT00222-1/journalimage?img=PIIS1546250104002221.gr1.lrg.gif&fig=fig1&kwhquery=&issn=1546-2501&ishighres=false&allhighres=false&free=yes','journalimage');)
