In females, menarche is the most significant corporal change during adolescence. Primary amenorrhea is defined as the absence of menstruation by the age of 15 with developed secondary sexual characteristics or three year after thelarche.4 There are several classifications of causes of primary amenorrhea, including anatomic defects, primary hypogonadism, hypothalamic causes, pituitary causes, chromosomal abnormalities and other endocrine gland disorders.5
The prevalence of 46, XY karyotype in females with primary amenorrhea, either with pure gonadal dysgenesis or complete androgen insensitivity syndrome is around 3–6%.6 Pure gonadal dysgenesis, also known as Swyer syndrome, may be recognized when there are not normally differentiated testes despite male karyotype. It has been reported that the mutation in several genes are responsible for Swyer syndrome, among which SRY appears to be the most significant one and responsible for 10–20% of cases.7 Patients with Swyer syndrome are typically tall-statured and with female genitalia. Another feature is hypergonadotropic hypogonadism with low levels of estrogen and AMH and high level of FSH, which results in poor breast development, amenorrhea, increased risk of cardiovascular disease.7 With regards to complete androgen insensitivity syndrome, tissues are not reactive to testosterone due to the mutation in gene encoding androgen receptor, although testes are developed and their hormone secretion function is preserved. Affected individuals are with the external female phenotype and genitalia due to the normal conversion of excessive testosterone to estrogen. However, Mullerian derivatives are not preserved and testes may be situated either in the abdominal cavity or throughout the inguinal canal or in the labia majora. Hormonal profiles usually show elevated testosterone and detectable estrogen concentrations.8
The clinical features in our patient presented in this report, including female external genitalia, presence of uterus, hypergonadotropic hypogonadism, low AMH level and 46, XY karyotype can be easily misdiagnosed as Swyer syndrome. However, when digging the past history of the patient, it was found that the appearance of 46, XY karyotype in the peripheral blood in this patient is due to the bone marrow transplant from a male donor. This clue can help to rule out the diagnosis of Swyer syndrome. There are two similar cases reported previously. One study reported a childhood cancer survivor with premature ovarian insufficiency and 46 XY karyotype in lymphocytes after chemotherapy and BMT from an unrelated male donor,9 and the other report showed a patient with primary amenorrhea and 46 XY karyotype after receiving BMT from her brother and chemotherapy due to acute myeloid leukemia.10 The authors from both reports also found a high likelihood of misdiagnosis of Swyer syndrome, which was similar to our report. Therefore, the comprehensive collection of detailed present and past medical history is pretty important for a correct diagnosis.
In this case presented, several possible causes may be contributing to the observed iatrogenic premature ovarian insufficiency. After repeated red blood cell transfusions, patients with thalassemia major may have ovarian impairment due to iron overload, when the transferrin-dependent system is inhibited through ferritin saturation pathway and excessive iron accumulation occurs through the non-transferrin bound iron (NTBI) pathway.11 Although the most common endocrinopathy in patients with thalassemia is the hypogonadism resulting from iron deposition in the hypothalamic and/or pituitary cells,12 it is also worth noting that iron overload may affect ovarian function directly as well. An earlier study has shown an inverse correlation between AMH level and NTBI,13 suggesting suspected ovarian tissue iron overload in women with thalassemia major. Another study also demonstrated that AMH level and antral follicle count are significantly decreased in women with transfusion-dependent thalassemia major compared with age-matched controls.12 These findings support a deleterious effect of iron overload on ovarian tissue, which may result in an increase in reactive oxygen species and the subsequent acceleration in follicular aging.14 An earlier study has found high redox activity in the ovarian follicular fluid from a woman with thalassemia major, which suggested that redox-active iron ions may mediate free radical production and induce ovarian tissue injury.15 Therefore, there is a need to better define the appropriate chelation regimens and antioxidant supplementations regarding reproductive function in women with thalassemia major receiving blood transfusion treatment. However, whether ovarian function is impaired by a direct effect of iron overload is not clearly understood yet.
Another important factor responsible for the ovarian impairment in this case may be BMT, including chemotherapy and/or total body irradiation (TBI). The extent of follicular impairment can be affected by the type of TBI protocol as well as the age receiving BMT. In terms of chemotherapy, busulfan appears to be the most gonadotoxic regimen, with reported prevalence of premature ovarian failure as high as 100%.16,17 Low-dose cyclophosphamide (200mg/kg) is considered to be much less gonadotoxic compared with other regimens, with good recovery rates of clinical ovarian function, particularly in women younger than 25 years old.18,19 In contrast, TBI appears to be a more toxic treatment prior to BMT and most patients undergoing TBI experience gonadal failure. Compared with TBI administration after puberty, TBI administered prior to puberty is reported to be less gonadotoxic and around 40–60% of patients experienced apontaneous puberty.20,21 This might be due to the higher number of non-growing follicles found in younger girls and some other particular anatomical or paracrine factors, which might lead to a higher resistance to fibosis implicated in the mechanisms of ovarian damage.22
To conclude, this is a case report of a patient presenting with primary amenorrhea, premature ovarian insufficiency and 46, XY karyotype in peripheral blood after receiving chemotherapy and BMT from her brother in childhood due to thalassemia major. It is important that gynecologists should be aware that not only the clinical manifestations, but also the detailed medical history are crucial for a correct diagnosis and the following treatment. In light of the relatively high prevalence of thalassemia, particularly in the southern China, protection of ovarian function should be considered for young girls who are going to have chemotherapy, total body irradiation and BMT.