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- Dania Al-Jaroudi, M.D
A 17-year-old girl presented to our gynecology clinic with secondary amenorrhea. She had been diagnosed with ALL at the age of 5 years, she received chemotherapy and radiotherapy over the following years. Her chromosomal analysis showed a karyotype of 46, XY.
Primary ovarian insufficiency is a disorder that is emotionally traumatic and bears lifelong consequences on fertility, bone and cardiovascular health (1,2), making it more challenging is its occurrence in adolescents. Previously the term premature menopause had been used and found to be incorrect; as about 50 % of women have intermittent ovarian function and may ovulate and conceive after this diagnosis (1,2,3). The diagnosis is made when women younger than 40 years, have four or more months of amenorrhea and two serum FSH levels taken one month apart in the menopausal range (2).
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Causes of primary ovarian insufficiency in adolescents include chromosomal abnormalities, premutation in the FMR1 gene for fragile X, or iatrogenic from chemotherapy or radiation therapy (1). Infiltrative, infectious processes and pelvic surgery are less common causes (1). Autoimmune disease is another cause, as around 4% of women will have adrenal or ovarian antibodies. Still the etiology remains unknown in many cases (3).
Although advances in oncology treatments have improved survival of childhood cancer, this came at the expense of ovarian function, increasing the risk of ovarian insufficiency and infertility (4). Morse et. al showed in a prospective observational study of ovarian function during cancer treatment of females aged 0 to 18 years that ovarian insufficiency occurred in chemotherapy treated prepubertal and pubertal patients regardless of menarche, age, diagnosis or chemotherapy given (5). Furthermore, females receiving radiotherapy below the diaphragm and/or stem cell transplant (SCT) had no recovery in their ovarian function followed for one and a half years from the end of their treatment (5).
Clinicians need to be sensitive in delivering the diagnosis of primary ovarian insufficiency to their patients (6). This diagnosis can be emotionally traumatic and emotional needs of the patient need to be addressed as should further support be available (6). Adequate information regarding the diagnosis should be given as according to Groff AA et al (6); most patients feel that inadequate information decreased their sense of control (6).
Our patient is a17-year old single girl who presented to our clinic with secondary amenorrhea. She had been diagnosed with acute lymphocytic leukemia (ALL) in 2002 at 5 years of age. Therapy began with hyperfractionated chemotherapy with two courses; course A: cyclophosphamide, vincristine, doxorubicin, and dexamethasone and Course B: methotrexate and cytarabine (HCVAD). She relapsed in 2007 and 2012 and was treated with methotrexate (MTX), dexamethasone (DEXA), vincristine, and L-asparagine. She then had total body radiation in 2012.
In July 2012, patient was referred to King AbdulAziz medical city at 15 years of age with pancytopenia, she was again given hyperfractionated chemotherapy with two courses; course A: cyclophosphamide, vincristine, doxorubicin, and dexamethasone and Course B: methotrexate and cytarabine (HCVAD).
After remission she was given busulfan/cyclophosphamide then she had stem cell transplant (SCT) from her full HLA matched sibling.
Patient had menarche at 11 years, after which she had regular menstruations for 4 years before she developed secondary amenorrhea. Progesterone challenge test was done with no response. Hormonal profile showed hypergonadotropic hypogonadism, normal thyroid function test and prolactin levels. Pelvic ultrasound showed normal, but small sized uterus and ovaries. Chromosomal analysis showed 46, XY, this confused her primary physician was unsure about the best plan of management. On further review of her previous investigations, her chromosomal analysis one-year back had been a normal female genotype. So with the stem cell transplant (SCT) from her HLA matched sibling her genotype and her whole cell line had changed. With the impression of premature ovarian insufficiency as her primary diagnosis, patient was started on cyclical hormonal therapy; estradiol valerate 2 mg, norgestrel 500 mcg (progyluton®, Bayer Health, Germany) for 6 months. On follow up after 2 months, she didn’t start progyluton because she thought she needs to start 5th day of cycle; proper counseling was done and patient was seen 2 months afterwards on hormonal therapy, calcium and vitamin D with withdrawal bleeds.
Objective: To report a case of primary ovarian insufficiency in 17 year old, single girl, who had ALL and was treated with chemo and radiotherapy, followed by bone marrow transplant.
Design: Case report.
Setting: King Abdulaziz Medical City
Patient(s): A patient diagnosed with primary ovarian insufficiency, after receiving chemo and radiotherapy for ALL. She later received bone marrow transplant from her HLA matched brother.
Intervention(s): Hormone replacement therapy.
Main Outcome Measure(s): After ruling out other causes, counseling and emotional support where given to the patient. She was then started on hormonal replacement therapy, calcium and vitamin D.
Result(s): Patient started hormonal therapy and was followed in the clinic.
Conclusion(s): This case describes a primary ovarian insufficiency in a girl post chemo and radiotherapy; it also describes a change in cell line following bone marrow transplant from her HLA matched brother.
Key Words: Secondary amenorrhea, primary ovarian insufficiency, Hormonal replacement therapy, stem cell transplant.
Acknowledgments: We would like to express our thanks to Dr. Hanan Dahlawi for providing care to the patient.
Conditioning with chemotherapy and radiotherapy prior to stem cell transplant (SCT) particularly with cyclophosphamide and total body irradiation will inevitably lead to primary ovarian insufficiency and infertility (7). The risk of primary ovarian insufficiency when patients receive busulfan and cyclophosphamide is about 100%, similar to what our patient has received (7).
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We report this case as this patient’s karyotype changed to a male karyotype following stem cell transplant (SCT) from her full HLA matched sibling. This led to a diagnostic confusion at first, and was later understood after her karyotype one year earlier was reviewed and genetist was consulted.
There was no similar cases reported in the literature, although numerous cases where reported on primary ovarian insufficiency in adolescents, and successful pregnancy thereafter. Therefore, we recommend to educate physician on changes occurring after stem cell transplant. Unfortunately, this patient was not offered fertility preservation options prior to her treatment; this again is another area of awareness that needs to be raised in physicians.
Nonetheless, this patient was offered counseling and hormonal therapy after she was referred to our out patient clinics. The aim of hormonal therapy in adolescents with primary ovarian insufficiency includes the relief of hypoestrogenic symptoms in addition to bone support, cardiovascular, and sexual health (8). Adolescents may need higher doses of estrogen than menopausal women to ensure adequate replacement and optimal bone health (8).
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