Early menopause in long-term survivors of cancer during adolescence

Byrne, Julianne; Fears, Thomas R.; Gail, Mitchell H.; Pee, David; Connelly, Roger R.; Austin, Donald F.; Holmes, Grace F.; Holmes, Frederick F.; Latourette, Howard B.; Meigs, J. Wister; Strong, Louise C.; Myers, Max H.; Mulvihill, John J.

doi:10.1016/0002-9378(92)91335-8

Cited by 384 publications

(128 citation statements)

References 23 publications

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“…However, although some females experienced spontaneous pubertal development, they carry a substantial risk of early menopause. Byrne et al 34 found a significantly increased risk of menopause during the early 20s occurring after alkylating agents and irradiation below the diaphragm, especially when both treatments were given together.…”

Section: Discussionmentioning

confidence: 99%

Ultrasound B-mode changes in the uterus and ovaries and Doppler changes in the uterus after total body irradiation and allogeneic bone marrow transplantation in childhood

Holm

Nysom

Brocks

et al. 1999

Bone Marrow Transplant

115

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Summary:Internal genitalia and uterine blood flow were assessed by ultrasound in 12 females 4.0-10.9 years after total body irradiation and allogeneic bone marrow transplantation for childhood leukaemia or lymphoma. Median age of the participants was 12.7 years (range 6.1-17.6) at bone marrow transplantation and 21.5 years (11.6-25.6) at the follow-up study. At follow-up all had entered puberty and 11/12 females had experienced the menarche. Eight females received sex steroid replacement therapy, three had spontaneous pubertal development and one woman experienced symptoms of estrogen deficiency. Median uterine and ovarian volumes were significantly reduced to ؊2.6 standard deviation scores (SDS) (؊6.3 to ؊0.6), P ‫؍‬ 0.002, and ؊2.6 SDS (؊4.8 to ؊0.5), P ‫؍‬ 0.002, respectively, compared with normal controls. Follicles were only detectable in two individuals. Uterine blood flow was impaired, as a systolic blood flow could be measured in 6/9 individuals, and a diastolic blood flow in 1/9 females. Our results indicate that the prescribed dosage of hormone replacement therapy, which was sufficient to induce bleeding and suppress other stigmata of premature menopause, was inadequate to generate normal uterine growth. In order to achieve uterine growth higher doses of hormone replacement therapy may be required. Our results confirm pelvic ultrasound as a reliable tool for investigation of internal female genitalia; however, in an infertility setting further tests are indicated. Keywords: BMT; TBI; childhood; uterus; ovary; uterine blood flow During the past two decades allogeneic bone marrow transplantation (BMT) has been used in the treatment of children with relapsed or very high risk leukaemia and lymphoma. Since many of these children become long-term survivors, the late effects of treatment are of major concern. Preparative regimens for BMT, high-dose chemotherapy alone or in combination with total body irradiation (TBI), may cause various endocrine abnormalities, 1-10 and ovarian failure Correspondence: K Holm, Department of Growth and Reproduction, Section 5064, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark Received 26 March 1998; accepted 5 September 1998 resulting in life-long need for sex steroid replacement therapy (HRT) and infertility is common. Recovery of ovarian function occurs especially when preparative regimens do not include TBI, 5-11 and cases of pregnancies resulting in successful deliveries have been reported even when preparative regimens have included TBI. [12][13][14][15][16][17][18][19][20] The progress of assisted reproduction and the availability of oocyte donation has made pregnancy a possibility in women without ovarian function, provided there is normal function of the uterus. However, once pregnancy has been achieved, other problems may occur. In patients treated for solid tumours abdominal irradiation with 20-30 Gy have caused irreversible damage to uterine musculature and blood flow 21 and a high risk of adverse pregnancy outcome, eg low birth weight and increased perinat...

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Section: Discussionmentioning

confidence: 99%

Ultrasound B-mode changes in the uterus and ovaries and Doppler changes in the uterus after total body irradiation and allogeneic bone marrow transplantation in childhood

Holm

Nysom

Brocks

et al. 1999

Bone Marrow Transplant

115

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“…5 Young women treated for Hodgkin's disease may be at risk of premature menopause. 7,18 Byrne et al 18 report a significantly increased relative risk of early menopause in cancer survivors treated with either radiotherapy or alkylating agents alone. According to these authors, 42% of women treated with alkylating agents and subdiaphragmatic radiotherapy were menopausal by the age of 31.…”

Section: Discussionmentioning

confidence: 99%

Ovarian function after autologous bone marrow transplantation in childhood: high-dose busulfan is a major cause of ovarian failure

Teinturier

Hartmann

Valteau‐Couanet

et al. 1998

Bone Marrow Transplant

194

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Summary:We studied pubertal status and ovarian function in 21 girls aged 11-21 years who had earlier received 1.2-13 years (median 7 years) high-dose chemotherapy and autologous BMT without TBI for malignant tumors. Ten of them were given busulfan (600 mg/m 2 ) and melphalan (140 mg/m 2 ) with or without cyclophosphamide (3.6 g/m 2 ). Eleven others did not receive busulfan. Twelve girls (57%) had clinical and hormonal evidence of ovarian failure. Among nine others who had completed normal puberty, six had normal gonadotropin levels, one had elevated gonadotropin levels and two had gonadotropin levels at the upper limit of normal. The 10 girls who received busulfan all developed severe and persistent ovarian failure. High-dose busulfan is therefore a major cause of ovarian failure even when given in the prepubertal period. These findings emphasize the need for long-term endocrine follow-up of these patients in order to initiate estrogen replacement therapy. Keywords: ovarian function; high-dose chemotherapy; bone marrow transplantation; busulfan; childhood Increasing numbers of children who receive hematopoietic stem cell transplants (HSCT) for malignancies now survive. It is therefore important to evaluate ovarian toxicity secondary to the therapeutic regimens. New chemotherapy protocols will have to aim towards effecting long-term survival with minimal late morbidity. Chemotherapy is used alone or in combination with total body irradiation. Total body irradiation, used in the preparative regimens for hematologic malignancies, is deleterious to gonadal function. 1,2 Myeloablative therapy consisting of cyclophosphamide, busulfan or melphalan, has been used as an alternative to avoid the side-effects of irradiation on endocrine functions and growth. 1,3,4 Cytotoxics are known to induce ovarian toxicity in adults, dependent upon type of agent, dosage, administration schedule and patient age. 5-7 Much less is known about the effects of high-dose chemotherapy on ovarian function in children. 2,8,9 We report an analysis of ovarian function in long-term survivors following myeloablative chemotherapy and bone marrow transplantation. Patients and methodsWe screened all long-term female survivors older than 11 years who had received high-dose chemotherapy and autologous bone marrow transplantation without abdominal or pelvic radiation for malignant tumors at Institut Gustave Roussy. Twenty-one girls fulfilled these criteria.At time of transplantation, they were aged 2-17 years (median 9 years). Pubertal development was evaluated clinically according to Tanner. 10 Fourteen girls were prepubertal (stage 1), two were undergoing puberty (stage 3) and five had regular menses (stage 5). No hormonal evaluation was carried out before chemotherapy, but pubertal stages of all the patients were appropriate for their age.The study took place 1.2-13 years (median 7 years) after bone marrow transplantation and discontinuation of chemotherapy. At time of study, girls were aged 11.5-21 years (median 14.5 years).Serum concentrations of 17...

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“…For these young patients, recovery of ovarian function and reproductive potential after treatment have become important quality-of-life issues. Various chemotherapeutic agents, particularly alkylating agents, have been identified as gonadotoxic, and pelvic or total body irradiation (TBI) can cause irreversible gonadal damage [3][4][5], potentially leading to infertility problems and premature ovarian failure (POF) [3][4][5][6][7][8][9]. This risk depends on the patient's age and follicle reserve, as well as the type and dose of drug received, and is not always easy to predict.…”

Section: Introductionmentioning

confidence: 99%

Is transplantation of a few leukemic cells inside an artificial ovary able to induce leukemia in an experimental model?

Soares

Saussoy

Sahrari

et al. 2015

J Assist Reprod Genet

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Early menopause in long-term survivors of cancer during adolescence

Cited by 384 publications

References 23 publications

Ultrasound B-mode changes in the uterus and ovaries and Doppler changes in the uterus after total body irradiation and allogeneic bone marrow transplantation in childhood

Ultrasound B-mode changes in the uterus and ovaries and Doppler changes in the uterus after total body irradiation and allogeneic bone marrow transplantation in childhood

Ovarian function after autologous bone marrow transplantation in childhood: high-dose busulfan is a major cause of ovarian failure

Is transplantation of a few leukemic cells inside an artificial ovary able to induce leukemia in an experimental model?

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