Investigation on the Occurrence of Premature Ovarian Insufficiency after Allogeneic Haematopoietic Stem Cell Transplantation and Prognosis Analysis - a single-center real-world cross-sectional study

doi:10.21203/rs.3.rs-8166217/v1

Introduction

: Hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment for patients with hematologic disorders; however, the pre-HSCT conditioning regimen may induce premature ovarian insufficiency (POI)—characterized by menstrual disorders and infertility—which significantly compromises female patients’ quality of life. This real-world cross-sectional study aimed to identify risk factors for POI by analyzing menstrual flow status, fertility changes, and determinants of perimenopausal symptoms in female patients following allogeneic HSCT.

Methods

Fifty-four female patients who underwent allogeneic HSCT at the Affiliated Hospital of Qingdao University from April 2012 to November 2023 were enrolled. Assessments including peripheral blood sex hormone level analysis and questionnaires were used to evaluate menstrual flow status, fertility changes, and determinants of perimenopausal symptoms. Risk factor analysis was primarily performed via binary logistic regression, columnar line chart models and receiver operating characteristic (ROC) curves.

Results

A total of 43 patients (78.18%) developed secondary POI after allogeneic HSCT, with a median age of 29 years (range: 5–39 years). Among the enrolled patients, 10 received the fludarabine + cyclophosphamide + antithymocyte globulin conditioning regimen, and 44 received busulfan (Bu)-based regimens. Binary logistic regression analysis revealed that older age (> 10 years) at transplantation and Bu-based conditioning regimens were risk factors for POI development post- allogeneic HSCT.

Conclusion

POI is common in female patients after allogeneic HSCT. Older age at transplantation and the use of busulfan (Bu)-based conditioning regimens may be key risk factors for post- allogeneic HSCT POI.

allogeneic hematopoietic stem cell transplantation

Premature Ovarian Insufficiency

conditioning regimen

menstruation and fertility

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is now a curative treatment option for many patients with malignant haematological and non-malignant haematopoietic disorders [1]。With improved survival rates and prolonged life expectancy among hematologic disorder patients undergoing allo-HSCT, more and more attention were paid on gynecological and obstetric issues in female allo-HSCT recipients [2]. Female patients with allo-HSCT are highly susceptible to injury to the reproductive system caused by radiotherapy and chemotherapy used in the condition regimen, leading to the development of premature ovarian failure(POF) or premature ovarian in-sufficiency (POI). This results in amenorrhoea, infertility, and perimenopausal symptoms such as hot flushes, restless, loss of libido, and so on[3]. Chronic graft-versus-host disease (cGVHD)invoved in genital system also have a serious impact on the sexual health and quality of life of patients[4].

According to several published data, girls undergoing allo-HSCT at a younger age, especially before puberty, have a greater probability of regaining a normal menstrual cycle and fertility after transplantation, but even then, the spontaneous pregnancy rate after allo-HSCT is less than 1%, especially after myeloablative conditioning regimen (MAC).

Myeloablative conditioning regimens have also been shown to be an important risk factor for the development of POI after allo-HSCT, with the incidence of POI about 95% after application of the MAC regimen[5] [6]. Busulfan (Bu)-based conditioning regimens were used in more than 50% of allogeneic HSCT cases in the last two years [7]. In the real world analysis, modified Busulfan/cyclophosphamide regime(mBuCy) is currently the most popular modification regimen for allogeneic haematopoietic stem cell transplantation in the country compared to traditional total body irradiation (TBI) treatment (59%) [8].

Although research on ovarian function in female patients after allo-HSCT is gradually being emphasised, there is still little research on the factors influencing the development of POI in female patients after allo-HSCT. The core needs of female patients, from a young woman's family planning to an older woman's management of menopause, require understanding and response.

This study assessed the risk factors for POI after allo-HSCT in female patients in a real-life world, including following-up of the patients' menstrual fertility and determination of their pregnancies and their outcomes, as well as exploring the clinical factors associated with the development of perimenopausal symptoms, in order to provide more patients, especially those who want fertility preservation, with a richer understanding and options for disease prognosis and fertility preservation measures with the help of their doctors.

2.1 Patients:

69 female patients treated with allo-HSCT from April 30th ,2012 to November 30th, 2023 at the Affiliated Hospital of Qingdao University were enrolled with the criteria as followings: (1) age < 40 years at the time of allo-HSCT; Exclusion criteria: (1) patients who had received more than 1 time of HSCT treatment, including auto-HSCT and allo-HSCT; (2) patients with POI, POF, or abnormal sex development or a history of ovarian surgery before transplantation. 69 patients who met the criteria, 8 were lost to follow-up, 7 failed to complete the questionnaire, and finally 54 patients completed the study, The flowchart is shown in Fig. 1. The median follow-up time after allo-HSCT was 4.8 years (range,1 ~ 8 years) in 54 patients. This study was approved by the Hospital Ethics Committee. Written informed consent was obtained from each subject, and in the case of minors, from parents/guardians.

2.2 Definitions of variables:

(1) Premature Ovarian Insufficiency (POI) is a clinical syndrome characterized by the loss of ovarian function before the age of 40. The diagnosis is made in women under 40 based on the combination of menstrual disturbances (primarily amenorrhea or oligomenorrhea) and elevated follicle-stimulating hormone (FSH) levels (> 25 U/L) on two occasions at least 4 weeks apart.[9]

(2) Menopausal symptoms were determined by the modified Kupperman Index ,which were classified as none (total score < 6), mild (6 ≤ total score ≤ 15), moderate (16 ≤ total score ≤ 30), and severe (total score ≥ 30)[10].

2.3 Study design:

This study was divided into two parts: (1) a study of the correlation between the incidence of POIs and different clinical factors, and (2) an analysis of the quality of life and post-transplant menstruation and fertility.

The first part collects information on blood disorders through the hospital database, including the patient's age at transplantation, type of blood disorder, chemotherapy lines before transplantation, donor-recipient relationship, gender of the donor, degree of HLA compatibility, conditioning regimen, type of grafts and acute/chronic GVHD status. The fertility parameters used were taken from the patients’long-term follow-up data, including the hormonal analysis of luteinising hormone (LH), follicle stimulating hormone (FSH) and oestrogen. The second part used an independently designed questionnaire to collect the patients' menstrual status before and after allo-HSCT, their fertility status, whether they had undergone fertility preservation measures, and whether they used hormone replacement therapy. The severity of menopausal symptoms was also assessed by the modified Kupperman Index. Data were collected by telephone or web-based questionnaires.

2.4 Statistical:

All statistical analyses were performed using a two-tailed test with a value of p < 0.05 being considered statistically significant. Categorical variables significance was analysed using chi-square test and Fisher's exact test. Logistic regression analysis was used to analyse the factors influencing the occurrence of POI after allo-HSCT in female patients, with corresponding receiver operating characteristic (ROC) curves plotted. The rms was utilised to generate the prediction model's scatter plot and calibration curve, thereby assessing the model's accuracy. All statistical analyses were performed using IBM SPSS software v27.0.

3.1 Baseline characteristics of patients：

The study included a total of 54 patients, with a mean age at transplantation of 25.6 years (5-39 years)，which distributed across age groups as follows: <10 years (n=6), 10-20 years (n=21), 21-30 years (n=15), and 31-39 years (n=21). 76%（23/54）of the patients had malignant haematological disorders, including acute myeloid leukaemia (AML，n=23) and acute lymphoblastic leukaemia (ALL,n=18), while the remaining 34% of the patients with benign haematological disorders, including aplastic anaemia (AA,n=12) and paroxysmal sleep haemoglobinuria (PNH,n=1). Forty-four patients (81%) received a Bu-based conditioning regimen (Flu+BUCY regimen in 4 cases and modified BUCY regimen in 40 cases). Malignant diseases are treated with modified BUCY regimen. FAC (fludarabine 150 mg/m2, CTX 120 mg/kg, ATG 10 mg/kg) conditioning regimen was used in 10 AA patients, and addition of BU with 3.2 mg/kg × 2 d were used in those with a disease duration of >=3 years, iron overload, hemihypoplasia, and other predicted implantation adverse factors. Baseline characteristics of the study cohort are shown in Table 1.

3.2 Correlation of POI incidence with different clinical factors：

43 patients (78.18%) occurred secondary POI after allo-HSCT. A comparison of the two groups revealed statistically significant disparities in age, pretreatment regimen, and primary diagnosis (p < 0.05). A positive correlation was identified between age grouping and secondary POI following allo-HSCT (r=0.379, P=0.003, Kendall tau-c correlation analysis.

3.3 Logistic regression analysis of factors influencing the development of POI after allo-HSCT :

All the patients were included in an unconditional logistic regression analysis model with whether they had a secondary POI after allo-HSCT (no=0,yes=1) as the dependent variable and age and conditioning regimen as independent variables，The results show that older age (>10 years old) at the time of receiving allo-HSCT and Bu-based conditioning regime are risk factors for POI after allo-HSCT in female patients. Patients were divided into subgroups according to age <10 years, 10-20 years, 21-30 years, and 31-39 years. For each 1-fold increase in age level, there was a 1.755-fold increase in the risk of developing POI (advantage ratio (OR) = 5.781, 95% confidence interval: 1.379,24.239). Patients with Bu-based conditioning regime (OR = 144.339) had an increased risk of POI, as shown in Table 2.

3.4 Development and Validation of a Nomogram Model for Predicting POI Risk in Female Patients after allo-HSCT

Based on the results of the logistic regression analysis mentioned above, the rms was used to create a nomogram for predicting the risk of POI in female patients after allo-HSCT. As shown in Figure 2, the patient's score on the nomogram increased significantly with higher age levels. Patients who received a Busulfan (BU)-containing preconditioning regimen saw their nomogram score increase by 94 points. To validate the predictive accuracy of the nomogram model, this study plotted its Receiver Operating Characteristic (ROC) curve. The ROC curve (Figure 3) yielded an Area Under the Curve (AUC) of 0.939 (P < 0.001, 95% CI: 0.758-0.976), indicating that the model has a high predictive power for the occurrence of POI. Furthermore, the model was calibrated, and a calibration curve was plotted (Figure 4). The calibration curve exhibited a slope close to 1, suggesting a strong agreement between the model-predicted risk of POI in female patients after allo-HSCT and the actual observed risk.

3.5 Menstrual and fertility status of female patients before and after allo-HSCT：

6 of 9 patients who did not have menarche before allo-HSCT had spontaneous menarche after allo-HSCT (66.67%), and 7 of the 45 patients who had menarche before allo-HSCT had spontaneous return of menstruation after allo-HSCT (15.56%). Of all 54 patients counted, only 1 patient had a successful natural pregnancy and delivery after allo-HSCT, as shown in Table 3.

Premature ovarian insufficiency (POI) is a clinical syndrome characterized by ovarian function decline in women under 40 years of age, manifesting as menstrual disorders (e.g., amenorrhea or oligomenorrhea) accompanied by elevated gonadotropin levels and reduced estrogen levels. After allo-HSCT, many females suffer POI due to conditioning regimens, pre-transplant chemotherapy, age at allo-HSCT and post-transplant complications, and only a very small number of these patients recover ovarian function [4]，It is a well-documented fact that POI-induced symptoms and subsequent infertility are prevalent concerns for long-term survivors and their partners following allo-HSCT. These issues have been shown to have a detrimental effect on the quality of life (QoL) of those affected[11]. Therefore, exploring the risk factors leading to POI after HSCT can help clinicians assess patients' ovarian function before transplantation and predict the extent of treatment-related damage to ovarian function, thereby providing guidance on fertility preservation.

Age-stratified analyses demonstrated that the incidence of POI was significantly lower in patients aged <10 years than in the other three age groups (Pearson correlation coefficient r=0.379, P=0.003), whereas no significant intergroup differences were observed in POI incidence among patients aged 10–20, 21–30, and 31–39 years. Additionally, the probability of POI was substantially higher in patients who received a busulfan (Bu)-based conditioning regimen (93.18%) than in those treated with Bu-free conditioning regimens (20.00%, P<0.001). Logistic regression analysis identified two factors that exerted a significant and independent influence on the durability of ovarian function following allogeneic hematopoietic stem cell transplantation (allo-HSCT): age at allo-HSCT and conditioning regimen. Consistent with prior relevant studies, age at the time of allo-HSCT is critical for post-transplant ovarian function. In the present study, only 1 out of 6 patients aged <10 years at allo-HSCT developed POI, whereas the remaining 5 patients (aged ≥10 years at allo-HSCT) maintained more regular menstrual cycles and normal sex hormone profiles. Prepubertal girls (<10 years old) have a higher likelihood of avoiding POI, in contrast to the irreversible nature of ovarian function impairment observed in adults. In a study of 35 girls who underwent hematopoietic stem cell transplantation during childhood and adolescence, Jadoul et al. reported that an age of ≤10 years at transplantation was significantly and independently associated with a higher rate of clinically confirmed persistent ovarian function at the time of evaluation [12]. Notably, the present study not only validated the findings of these aforementioned studies but also identified that a younger age at allo-HSCT acts as a significant protective factor, particularly among patients who received a busulfan (Bu)-based conditioning regimen. Stratifying patients based on the presence or absence of Bu in the conditioning regimen, our results showed that among patients who received a Bu-based conditioning regimen, the vast majority of those aged >10 years developed irreversible premature ovarian failure (97.56%), whereas 66.67% (2/3) of those who received a Bu-based conditioning regimen before the age of 10 years experienced spontaneous menarche. Subgroup analyses further revealed that in the Bu-containing group, the incidence of POI in the <10-year age group was significantly different from that in the other three age groups (10–20, 21–30, and 31–39 years); however, no such difference was observed in the Bu-free group. Importantly, it should be emphasized that while a younger age confers protective effects against POI following allo-HSCT, this protective range does not extend to adolescence.

Our data demonstrate that all female patients aged 10–20 years who received a busulfan (Bu)-based conditioning regimen developed POI following allogeneic hematopoietic stem cell transplantation (allo-HSCT) (100%). Consistent with this, results from a multicenter study by Chabut et al. — involving 178 female patients who were <18 years old at diagnosis — showed that over 80% of patients who underwent HSCT at ≥10.9 years of age developed POI, and the risk of POI was significantly higher in patients who received HSCT during adolescence than in those who underwent transplantation in childhood[13]. Rather than benefiting from the protective effect of young age, peripubertal patients at the time of allo-HSCT experienced a more pronounced impact of allo-HSCT on ovarian function, as this period represents a critical stage in reproductive system development. This protective effect on prepubertal ovaries may be attributed to the higher number of non-growing follicles (NGFs) present in young girls. Sudies have demonstrated a strong negative correlation between age and the number of NGFs (a marker of ovarian reserve) [14] [15] [16]. Older females have a diminished pool of primordial follicles, rendering them more vulnerable to the damaging effects of chemotherapeutic agents. Consequently, younger patients who receive a Bu-based conditioning regimen have a lower incidence of POI.

Indeed, alkylating agents are responsible for the highest age-adjusted odds ratio of ovarian failure rates[15]. Of the alkylating agents, BU is the most gonadotoxic[17], while the BU-based conditioning regimens is also another important risk factor for premature ovarian Insufficiency in addition to age[18] [19]. Borgman et al. conducted a retrospective study involving seven centres in Europe and demonstrated that median LH and median FSH values were significantly higher in the group of female participants treated with BU compared to those who were not treated with BU. Receiving BU treatment (OR 47.4; 95% CI 5.4 ~ 418.1) significantly increased the risk of infertility [20]. In a study of 55 post-transplant female subjects, Su et al. found that the probability of POI was significantly higher in patients who received a BU-based conditioning regimen (96%) than in those who received other regimens (53.3%; P < 0.001)[21]. In contrast, only 3 patients out of all 54 patients in our statistics who received a BU-based conditioning regimen are currently considered no POI, receiving a BU-based conditioning regimen leads to a significantly increased risk of ovarian decline and premature menopause in female patients (93.18%, p<0.001).

However, in patients with aplastic anemia (AA) — who are at higher risk of poor graft function (PGF) — busulfan (BU) is frequently incorporated into the conditioning regimen in clinical practice to reduce the incidence of PGF[22] [23]. Given the long-term impacts of BU on reproductive function, we need to rethink whether the inclusion of BU in the conditioning regimen remains necessary for young female patients. Further clinical data are required to address this question.

Notably, a 29-year-old patient with acute myeloid leukemia (AML) who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) received a myeloablative conditioning (MAC) regimen before transplantation. Without any pre-transplant fertility preservation measures, this patient achieved natural conception and successful delivery in the 4th year after allo-HSCT. In previous studies, most cases reporting post-allo-HSCT pregnancy involved patients under 20 years of age at transplantation, and the majority of these patients received a reduced-intensity conditioning (RIC) regimen. In contrast, few spontaneous pregnancies have been documented in patients over 20 years of age with hematologic malignancies who received the MAC regimen. This case further suggests that although most post-pubertal female patients treated with the MAC regimen develop amenorrhea or even infertility, a subset of patients still retain ovarian function to varying degrees [24]. Additionally, several studies have demonstrated that higher estrogen (E2) levels may predict ovarian function recovery [25].

We also investigated post-transplant menopausal symptoms in 54 patients using a questionnaire with the Kupperman Scale; symptoms were categorised as absent, mild, moderate, or severe according to standard criteria, and detailed data are presented in Table 3. The results demonstrated a significant association between Kupperman score grades, age at transplantation, and the occurrence of chronic graft-versus-host disease (cGVHD)—a finding that differs from those reported by Su et al [21]. Specifically, four patients were assessed to have severe menopausal symptoms, including but not limited to severe insomnia and sensory disturbances; additionally, a total of 7 patients reported vaginal stenosis or atrophic vaginitis, which can be diagnosed as genital cGVHD based on clinical signs [4].

Regarding interventions for POI-related symptoms, hormone replacement therapy (HRT) has been widely shown to effectively alleviate multiple symptoms of gonadal failure [26] [27]. The International Menopause Society (IMS) states that women with POI should be offered hormone therapy (HT) until the average age of natural menopause (approximately 51 years), unless contraindicated[28]. Our questionnaire survey revealed that only 11 of the 43 patients who had developed POI (25.58%, 11/43) received HRT after allo-HSCT. This low rate, to some extent, reflects the extremely insufficient current awareness of ovarian function protection among patients in China.

Of all gynecological complications associated with allogeneic hematopoietic stem cell transplantation (allo-HSCT), sexual dysfunction and infertility are the most prevalent long-term issues among female survivors [6]. Most of the patients who have undergone the MAC pre-treatment programme and who want to have children of their own need assisted reproduction techniques (ART) [29]. Among the enrolled patients, only one had undergone OTC as a fertility preservation intervention before allo-HSCT; this patient subsequently regained regular menstrual cycles and normal sex hormone levels, and successfully achieved natural conception—with no signs of disease recurrence to date. Overall, the current post-allo-HSCT pregnancy rate remains low. Therefore, it is of paramount importance for hematologists to inform female patients (particularly young women) in need of allo-HSCT about infertility risks associated with treatment, and to offer appropriate fertility preservation options.

A limitation of this study is the small sample size due to its single-institution design. Prospective multicenter studies are warranted to mitigate potential bias and enroll a more representative patient population. Subsequently, we aim to further elucidate the impact of allo-HSCT on ovarian function by enrolling larger cohorts and incorporating long-term follow-up data.

The incidence of premature ovarian Insufficiency post-allo-HSCT was 78.18%, advanced age at transplantation and busulfan-based conditioning regimens were identified as primary risk factors for POI, with patient age demonstrating predictive value for POI occurrence. And younger patients have a lower incidence of POI when they receive a BU-based conditioning regimen. Patients who were older at HSCT and those who developed chronic graft-versus-host disease (cGVHD) post-HSCT exhibited higher Kupperman index scores. To date, ovarian tissue cryopreservation (OTC) appear to be the only effective fertility preservation options, though larger studies in survivor populations are still needed. The results of this study may provide clinicians with valuable information for counselling on ovarian function in patients with HSCT.

Data availability statement

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation. The data that support the findings of this study are openly available in Figshare at https://doi.org/10.6084/m9.figshare.30344926

Ethics statement

This study was approved by the Medical Ethics Committee of The Affiliated Hospital of Qingdao University (Project no.αYFYWZLL30232) and was conducted in accordance with the principles of the Declaration of Helsinki. Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.

Author contributions

Chenyu Shi conducted the majority of the experiments, analyzed the data, and wrote the original draft of the manuscript. Xiaodan Liu designed the experimental methodology, validated the results, and is responsible for coordinating future revisions and managing the manuscript submission process. Wei Wang conceived and supervised the research project and provided critical revisions to the manuscript for important intellectual content. Hui Wang and Tingxuan Wang provided technical assistance, contributed to data curation. All authors have read and approved the final version of the manuscript.

Acknowledgments

The authors thank the patients who volunteered to participate in the study.

Conﬂict of interest

The authors declare that the research was conducted in the absence of any commercial or ﬁnancial relationships that could be construed as a potential conﬂict of interest.

Funding

The authors declare that this research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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TABLE 1 Patient baseline characteristics and incidence of POI correlated with different clinical factors

	Number(%)	POI Number/Proportion(%)	statistical value	P
Age at allo-HSCT <10 10-20 21-30 31-39	6（11.11%） 12（22.22%） 15（27.78%） 21（38.89%）	1（16.67%） 10（83.33%） 12（80.00%） 20（95.24%）	17.921	<0.001
Disease type			10.538	0.005
AML	23（42.59%）	20（86.96%）
ALL	17（31.48%）	16（94.12%）
AA/PNH	14（25.93%）	7（50.00%）
Chemotherapy regimen Before allo-HSCT			2.831	0.243
0-5	35（64.81%）	27（77.14%）
6-10	14（25.93%）	13（92.86%）
>10	5（9.26%）	3（60.00%）
Type of allo-HSCT			3.209	0.201
Matchedsibling	27（50.00%）	22（81.48%）
Haploidentical	17（31.48%）	15（88.24%）
Unrelated	10（18.52%）	6（60.00%）
HLA match			1.650	0.199
5/10-9/10	24（44.44%）	21（87.50%）
10/10	30（55.56%）	22（73.33%）
Donor sex			0.300	0.584
Men	38（70.37%）	31（81.58%）
Women	16（29.63%）	12（75.00%）
Conditioning regimen			27.029	<0.001
Flu+BUCY	4（7.41%）	4（100.00%）
mBUCY	40（74.7%）	37（92.50%）
Flu+CY	10（18.52%）	2（20.00%）
Graft species			0.610	0.737
PB	39（72.22%）	32（82.05%）
PB+BM	12（22.22%）	9（75.00%）
Others	3（5.56%）	2（66.67%）
Recurrent/refractory			0.204	0，,62
yes	12（22.22%）	9（75.00%）
no	42（77.78%）	34（80.95%）
aGVHD grade			1.256	0.740
0	32（59.26%）	24（75.00%）
I	12（22.22%）	10（83.33%）
II	9（16.67%）	8（88.89%）
III-IV	1（1.85%）	1（100.00%）
cGVHD			2.912	0.088
yes	22（40.74%）	20（90.90%）
no	32（59.26%）	23（71.86%）

TABLE 2 Logistic regression analysis of factors influencing the development of POI after allo-HSCT

Factors	B	standard error	Waldχ2	P	OR		95% CI
Age at allo-HSCT	1.755	0.731	5.757	.016	5.781	[1.379,24.239]
Conditioning regimen	4.972	1.574	9.985	.002	144.339	[6.607,3153.344]
Constant	-4.791	1.939	6.104	.013	.008

TABLE 3 Menstrual and menopausal symptoms in patients before and after allo-HSCT

	number（%）	age
Menstruation before allo-HSCT
No menarche	9（16.67）	8.6±2.2
Regular menstruatio	39（72.22）	28.8±11.6
Irregular menstruation	6（11.11）	30.8±11.6
Menstruation after allo-HSCT
Lack of spontaneous menstruation / No menarche	41（75.93）	28.0±9.4
Menstrual relapsea but irregular	5（9.26）	23.8±5.1
Spontaneous menstrual relapsea	8（14.81）	14.6±8.7
Kupperman score
No	22（40.74）	17.8±10.8
Mild	17（31.48）	28.1±7.5
Moderate,	11（20.37）	34.5±4.6
Severe	4（7.41）	34.0±4.2
sex life
No	17（31.48）	11.9±4.4
as before	14（25.93）	30.4±6.7
Decreased sexual life	13（24.07）	32.8±4.6
loss of sexual life	10（18.52）	33.0±6.3
hormone replacement therapy
Yes	17（31.48）	24.8±8.0
No	37（68.52）	26.1±12.0

No competing interests reported.

Investigation on the Occurrence of Premature Ovarian Insufficiency after Allogeneic Haematopoietic Stem Cell Transplantation and Prognosis Analysis - a single-center real-world cross-sectional study

Status:

Version 1

Abstract

Introduction

Methods

Results

Conclusion

Figures

1 Introduction

2 Method

2.1 Patients:

2.2 Definitions of variables:

2.3 Study design:

2.4 Statistical:

3 RESULT

4 Disscussion

Conclusion

Declarations

References

Tables

Additional Declarations

Status:

Version 1