Menarche is an important clue for female puberty onset and also serve as a milestone in the process of female sexual development. The age at menarche (AAM) could reflect the time of female development and maturity. It correlates with reproductive health problems and social psychological13,14. In 2005, the average AAM in China was 12.76 years old, and that of Zhejiang province was 12.6, and there is a tendency to advance year by year15,16. The proportion of irregular menstruation in the same epidemiological survey was 16.41~22.61%17. In our cohort, menarche was significantly delayed, and the proportion of irregular menstruation was significantly increased compared to the general population. We found that WD was associated with delayed menarche and irregular menstruation. The menarche and menstrual cycle are dependent on sex hormone homeostasis. In the general population, spontaneous abortion rates ranged from 10–20%18. Notably in our cohort, spontaneous abortion rates were significantly high as 46.2%. The finding showed that WD could be closely related to abnormal conception. Among 37 WD patients, PRL, P and SHBG were the most affected, followed by T, FSH and LH. These metabolic disorders could be involved in irregular menstruation and abnormal delivery.
There were few studies on menstruation, sex hormones and pregnancy in WD patients. In 1991, the woman experienced 7 unexplained recurrent miscarriages from 21 to 26 years old19. Tarnacka et al. investigated the miscarriage, premature delivery, and stillbirth in 46 women with WD via questionnaires, and found that the proportion of spontaneous abortions between the treatment group and non-treatment group was 26.6% and 26% respectively, higher than the baseline proportion in Polish20. Sinha et al. also found that the spontaneous abortion rate was significantly higher with 40.7%21. The retrospective multi-center study in Germany found that the presence of cirrhosis at initial diagnosis of WD was not associated with a significant increase in spontaneous abortion compared with non-cirrhosis patients22. Therefore, combined with our cases accompanying abnormal pregnancy, when recurrent miscarriage and premature delivery could not be explained by gynecological related diseases, WD screening could be necessary.
At present, the causes of abnormal sex hormone, pregnancy and delivery in WD remained elusive. Arieh et al. analyzed hormone levels in 4 WD patients with obvious menstrual abnormalities, and concluded that the menstrual and ovulation dysfunction could be caused by the aromatase activity due to copper deposition23. Moreover, the previous studies demonstrated that copper was prone to accumulate in the maternal side of the placenta among WD patients, thereby leading to placental abruption, irregular menstruation, and even infertility24,25. Excessive copper deposition in the uterus could also result in repeated abortion in the early trimester. Moreover, there were reports on the successful pregnancy and childbirth after copper-exhaustion treatment. Additionally, deposited copper could affect the function of the hypothalamic-pituitary-ovarian (HPO) axis, and lead to delayed menarche, irregular menstruation, repeated miscarriage, and even infertility. However, other causative factors such as liver involvement, endocrinal disorders and anemia may be also responsible for the cause. Cirrhosis may lead to decreased estrogen inactivation ability and increased estrogen level. Moreover, anemia due to splenomegaly could also induce the pregnancy difficulties and menstrual disorder26.
In sum, we systematically described the sex hormone levels, menstrual history, pregnancy and childbirth history among 37 Chinese WD patients. We found that the ratio of delayed menarche, abnormal menstrual cycle, recurrent miscarriage, and premature delivery in WD patients was high, followed by abnormal sex hormone levels. These abnormalities could be related to the copper deposition in the gonad and liver cirrhosis. However, the specific mechanism still remained unknown. Combined the previous studies and our experience, we concluded that the reproductive system involvement in WD could be not rare, especially in untreated WD patients. The finding emphasized that early WD diagnosis is of vital importance due to its curability. The timely and individualized treatment might reverse the reproductive abnormalities. We need to realize that amenorrhea and recurrent abortions could precede the onset of typical manifestations in WD patients. Therefore, the affected patients should be evaluated for WD, especially accompanied by liver cirrhosis with unknown etiology.