Menstrual patterns and gonado-sexual health following hematopoietic transplant in reproductive age women and the role of hormone replacement therapy

Abstract

Background:

Menstrual patterns, reproductive sequelae, sexual health, and the role of hormone replacement therapy (HRT) among women following hematopoietic stem cell transplantation (HSCT) remain underexplored. This study evaluated menstrual resumption, ovarian reserve, fertility outcomes, sexual function, and attitudes towards HRT among women who underwent HSCT.

Methods:

This single-centre retrospective, cross-sectional analysis included women aged 18-45 years who had undergone HSCT for haematological malignancies and were on follow-up of at least 6 months post-HSCT. Data collected encompassed demographic details, disease characteristics, prior treatments, and transplant details. Menstrual patterns, anti-Müllerian hormone (AMH) levels, antral follicular counts (AFC), and the female sexual function index (FSFI) were measured among HSCT recipients at the time of study recruitment and compared with 30 age-matched healthy controls. Women with premature ovarian insufficiency (amenorrhea and follicle stimulating hormone [FSH] > 40 IU/L) were offered HRT. Among women who were administered HRT, 6 months follow-up menstrual resumption rates and FSFI assessments were done.

Results:

Among the 30 women enrolled, 86.6% (26/30) of patients had normal menstruation pre-HSCT, which declined to 23% (7/30) post-HSCT (p < 0.001). The median AMH level in the cases was 0.01 ng/mL (Range: 0.01-0.76), which was significantly lower than that of the controls (median: 2 ng/mL, range: 0.11-8.11). The AFC (median: 0, range: 0-5) was also significantly lower in HSCT recipients compared to controls (median: 11, range: 3-19) (p < 0.001). None of the HSCT recipients exhibited normal ovarian reserve post-HSCT. The proportion of patients with AMH levels above 0.01 ng/mL was higher in the subgroup that had return of spontaneous menses (n=5/7, 71.4%) compared to the subgroup that did not have return of menses (n=4/23, 17.4%); p=0.01. Similarly, the proportion of patients with an AFC greater than 1 was higher in the subgroup that resumed menstruation (6/7, 85.7%) compared to those who did not resume menstruation (3/23, 13%); p < 0.001. Among women desiring pregnancy, two achieved spontaneous conception resulting in healthy live births. A majority (24/26, 92.7%) of sexually active women exhibited sexual dysfunction (FSFI < 26.5) post-HSCT. HRT was offered to 23 women with premature ovarian insufficiency; however, 52.2% refused therapy. Among those who received HRT for at least six months, a significant improvement in the FSFI score was observed (p < 0.03).

Conclusions:

Ovarian and sexual dysfunction are frequent in post-HSCT women; a subset resumes spontaneous menstruation. Spontaneous conceptions may be observed despite low ovarian reserve markers. HRT may have a potential role to improve sexual and menstrual functions.

Introduction

Treatment of hematolymphoid malignancies frequently employs the use of hematopoietic stem cell transplant (HSCT)¹. With the increasing access to hematopoietic stem cell transplantation (HSCT), an increasing proportion of women of childbearing age are currently undergoing HSCT². Remission induction therapies prior to HSCT, the HSCT procedure itself, and other peri-transplant complications are known to affect ovarian and menstrual functions adversely³. Even among the patients who resume menstrual cycles, there is a high incidence of infertility, early menopause, and sexual dysfunction¹. As a result, the fulfilment of desired parenthood remains an unmet need in a significant proportion of these patients following HSCT³. All these factors are also known to have a significant detrimental impact on the quality of life of long-term female HSCT survivors⁴.

Despite these known consequences, at present, there are limited data on fertility assessment in young female survivors with haematological diseases after allogeneic HSCT⁵. The strategies for assessing residual ovarian function in female cancer survivors also remain heterogeneous. Anti-Müllerian hormone (AMH) levels may be superior to traditionally used follicle stimulating hormone (FSH) levels for assessing premature ovarian insufficiency⁶. There is limited data relating post-treatment AMH levels, antral follicular counts (AFC), and their quantitative predictive values to future fertility potential in HSCT recipients across various conditioning platforms⁷. Hormone replacement therapy (HRT) can improve menstrual and sexual functions; however, the safety, efficacy, and barriers to widespread utilization of HRT among HSCT survivors are not well studied⁸. The prevalence of sexual dysfunction and attitudes of HSCT-recipient women towards acceptance of HRT and its impact remains unknown. In the current study, we report our findings on menstrual pattern changes, ovarian reserve assessment using AMH and AFC, sexual function post-HSCT, attitudes towards HRT, and their impact on sexual function in HSCT-recipient women from our centre.

Materials and Methods

The study was a single, hospital-based, retrospective, cross-sectional analysis comparing HSCT recipients with age-matched healthy controls, conducted in women aged 18-45 years with hematolymphoid malignancies. The study recruited cases from women who attended the post-transplant follow-up clinic between May 2023 and December 2024. Thirty age-matched healthy women attending a family planning clinic during the same period were recruited as controls. Patients with active grade 3 or 4 graft versus host disease, disease relapse at the time of recruitment, or who were less than 6 months post-HSCT were excluded. The study was approved by the Institutional Ethics Committee (The IEC approval number: IEC-INT/2023/MD-2019). Informed consent was obtained from all adult subjects and from the parents of patients who were less than 18 years of age. Baseline pre-HSCT demographic characteristics, details of underlying hematolymphoid malignancy, anti-cancer therapy treatment received prior to HSCT, and transplant characteristics were retrospectively collected. Additionally, details of the menstrual history prior to and following HSCT were recorded. For the assessment of ovarian reserve, AMH levels and AFC were measured on day 2 of the menstrual cycle in menstruating females, and on any day in amenorrhoeic females. AMH was tested using an electrochemiluminescence immunoassay (ECLIA) E-810 on a Cobas e-immunoassay analyzer (Roche Diagnostics). AFC analysis was done by a transvaginal ultrasound, using a transducer of 5-7.5 MHz to calculate the sum of follicles of size 2 to 10 mm in both ovaries. Women with AMH levels < 1.2 ng/mL and/or AFC < 5 were considered to have poor ovarian reserve, as per the Patient-Oriented Strategies Encompassing IndividualizeD Oocyte Number (POSEIDON) criteria⁹. All women with premature ovarian insufficiency (having amenorrhea/infrequent menses and FSH > 40 IU/L) were offered HRT with 2 mg oral estrogen (Estradiol valerate) once daily for days 1-28 and 10 mg oral progesterone (Medroxy Progesterone Acetate) once daily for 10 days in a month for at least 6 months. To analyze sexual function among the HSCT recipients, the female sexual function index (FSFI) (Annexure 1) questionnaire was administered to all participants at the time of study enrollment, prior to starting HRT. A total score < 26.5 was taken as indicative of sexual dysfunction. All patients who were started on HRT were followed up monthly in the HSCT follow-up clinic for assessment of adherence and side effects of HRT. To study the impact of HRT on female sexual function, a follow-up FSFI score was analyzed among eligible participants who had received at least 6 months of HRT.

Statistical Analysis

The statistical analysis was conducted using IBM SPSS (Statistical Package for the Social Sciences) version 21. A chi-square test was used to check the association between categorical variables, while Fisher's exact test was applied when the expected cell frequency was < 5. Quantitative variables were assessed using mean, median, and standard deviation. The Shapiro-Wilk test, Kolmogorov-Smirnov test, and normality plot were used to check normality and for equality of variance Levene's test was used. An independent t-test was used to compare means for normally distributed data, while the Mann-Whitney U test was applied when the assumption of the t-test was violated.

Results

Demographic characteristics

Over 18 months, 30 cases and an equal number of age-matched healthy controls were recruited. The baseline disease characteristics are depicted in Table 1. The mean age of HSCT recipients at the time of study enrollment was 36.5 ± 5.8 years. One third of the HSCT recipients were nulliparous. Sixty per cent (18/30) of cases were autologous HSCT recipients, 36.6% (n=11) were allogeneic HSCT recipients, while one patient of Hodgkin's lymphoma had received a transplant twice (autologous followed by allogeneic transplant). Except for 5 patients, all patients had received myeloablative conditioning. Prior to HSCT, 53.3% (n=16) received a single line of anti-cancer therapy, 23.3% (n=7) received two lines, while another 23.3% (n=7) received more than two lines of therapy prior to HSCT. The median interval from HSCT to recruitment was 16.5 months (range: 6-168 months).

Table 1. Baseline characteristics in study population.

VARIABLES	GROUPS		CASES (total: 30) n (%)	CONTROLS (total: 30) n (%)	p-VALUE
DEMOGRAPHIC DETAILS
Age at recruitment (Years)	26-30		6 (20.0)	6 (20.0)	1.000a
	31-35		8 (26.7)	8 (26.7)
	36-40		7 (23.3)	7 (23.3)
	41-45		9 (30.0)	9 (30.0)
	Mean ± Standard deviation; (Range)		36.37 ± 5.82; (26-45)	36.33 ± 5.80; (26-45)	0.982c
Age at diagnosis (Years)	Mean ± Standard Deviation; (Range)		31.77 ± 4.77; (24-39)	-	-
Age at HSCT (Years)	Mean ± Standard Deviation; (Range)		33.60 ± 5.20; (24-44)	-	-
BMI (Kg/m2)	18.5-22.9		9 (30)	6 (20)	0.236b
	23.0-24.9		6 (20)	3 (10)
	25.0-29.9		12 (40)	20 (66.7)
	>=30.0		3 (10)	1 (3.3)
Parity	Nulliparous		10 (33.3)	1 (3.3)	0.03b
	Multiparous		20 (66.7)	29 (96.7)
Education	Matriculate		26 (86.7)	27 (90)	0.50a
	High School or more		4 (13.4)	3 (10)
DISEASE AND TRANSPLANT CHARACTERISTICS
Primary hematologic disease	Hodgkin Lymphoma		8 (26.7)	-	-
	Multiple Myeloma		8 (26.7)	-
	Acute Leukemoid Lymphoma		4 (13.3)	-
	Acute Myeloid Lymphoma		3 (10.0)	-
	Chronic Myeloid Lymphoma		3 (10.0)	-
	Diffuse Large B Cell Lymphoma		2 (6.7)	-
	Myelodysplastic Neoplasm		2 (6.7)	-
Type of HSCT	Autologous		18 (60)	-	-
	Allogeneic	MSD	10 (33.3)	-
		MUD	-	-
		Haploidentical	1 (3.33)	-
	Dual		1 (3.33)	-
Conditioning regimen	Autologous HSCT	BEAM	10 (33.3)	-	-
		High dose Melphalan	8 (26.7)	-
	Allogeneic HSCT	Cy-TBI	3 (10)	-
		Flu-TBI	1 (3.3)	-
		Bu-Cy	2 (6.7)	-
		RIC (Flu-Mel)	5 (16.7)	-
	Dual	BEAM; RIC (TBI-Flu-Cy)	1 (3.3)	-
Number of lines of chemo-immunotherapy received prior to HSCT	One		16 (53.3)	-	-
	Two		7 (23.3)	-
	Three		2 (6.7)	-
	More than three		5 (16.7)	-

HSCT, hematopoietic stem cell transplantation; BMI, body mass index; MSD, matched sibling donor; MUD, matched unrelated donor; BEAM, BCNU (carmustine), etoposide, ara C (Cytarabine), melphalan; Cy-TBI, cyclophosphamide-total body irradiation; Flu-TBI, fludarabine-total body irradiation; Bu-Cy, busulphan-cyclophosphamide; RIC, reduced intensity conditioning; Flu-Mel, fludarabine-melphalan; TBI-Flu-Cy, total body irradiation-fludarabine-cyclophosphamide

a: Chi-Square Test, b: Fisher’s Exact Test, c: Independent t-test

Menstrual cycle patterns among HSCT recipients and their association with markers of ovarian reserve

Table 2 presents the patterns of menstrual resumption in the study population, as defined by the international federation of gynecology and obstetrics (FIGO) 2018 criteria recommendations¹⁰. About 86.6% (26/30) of cases had a normal menstrual cycle in the immediate pre-HSCT period. Among the remaining four patients, two had frequent, irregular, prolonged, and heavy menses, one had oligomenorrhea, while one was already amenorrheic before HSCT. At the time of study enrollment post-HSCT, only 23% (7/30) of patients spontaneously resumed their cycles. Among the seven patients who resumed menstruation, six patients had received myeloablative autologous stem cell transplant. Of these, 2 had infrequent cycles with shortened duration and reduced bleeding, one had frequent and irregular cycles with prolonged, heavy bleeding, another had regular but prolonged heavy bleeding, while the remaining 3 had regular cycles with normal frequency, duration, and amount of bleeding. A statistically significant difference was observed in the menstrual patterns before and after HSCT (p < 0.001), signifying the impact of peri-transplant interventions on the menstrual cycles. Table 3 summarises the markers of ovarian reserve in the study population in comparison to healthy control subjects. The median AMH levels in the cases were 0.01 ng/mL (range: 0.01-0.76), which was significantly lower than those of controls (median value: 2 ng/mL, range: 0.11-8.11). None of the patients had a normal AMH level (above 1.2 ng/mL). The majority of patients had an AFC below 5 among cases (28/30, 93.3%) that were significantly different from controls (1/30, 3.35%), p < 0.001. Seventy per cent (21/30) of cases had solid atrophic ovaries with no visible follicle. Despite low AMH levels (1.2 ng/mL) in all patients, 7/30 experienced spontaneous resumption of menses after HSCT. The median time to return of menses was 6 (range: 4-18) months among these patients. Supplementary Table 1 depicts a comparison of several parameters among the patients who had return of menstruation post-HSCT versus those who did not. Among the five patients who received a cumulative dose of cyclophosphamide greater than 100 mg/kg, none had spontaneous return of menses, although the difference was not statistically significant. Moreover, among these 5 patients, 2 had also received busulfan in their conditioning regimen, one had received total body irradiation (TBI), and the remaining two had received BCNU, etoposide, arabinoside C, melphalan (BEAM) conditioning, which may have contributed to gonadotoxicity. The proportion of patients who had AMH levels above 0.01 ng/mL was higher in the subgroup who had spontaneous resumption of menses (n=5/7, 71.4%) as compared to the subgroup who did not have resumption of menses (n=4/23, 17.4%); p=0.01. Similarly, the proportion of patients who had AFC > 1 was higher (6/7, 85.7%) in the subgroup who resumed menstruation as compared to those who did not resume menstruation (3/23, 13%); p < 0.001.

Table 2. Comparison of menstrual patterns before and after HSCT among HSCT recipients (n=30).

PARAMETERS			Before HSCT (total: 30 cases) n (%)	After HSCT (total: 30 cases) n (%)	p-VALUE*
Frequency of menstruation	Normal	Normal (24-36days)	26 (86.6)	4 (13.3)	<0.001
	Abnormal	Frequent (<24days)	2 (6.7)	1 (3.3)
		Infrequent (>36days)	1 (3.3)	2 (6.7)
		Complete Amenorrhea	1 (3.3)	23 (76.7)
Cycle-to-cycle variation (shortest to longest cycle)	Normal	Regular (7-9days)	28 (93.3)	6 (20)	<0.001
	Abnormal	Irregular (>8-10days)	1 (3.3)	1 (3.3)
		Complete Amenorrhea	1 (3.3)	23 (76.7)
Duration of blood flow	Normal	Normal (4-8days)	27 (90)	3 (10)	<0.001
	Abnormal	Prolonged (>8days)	2 (6.7)	2 (6.7)
		Shortened (<4days)	0	2 (6.7)
		Complete Amenorrhea	1 (3.3)	23 (76.7)
Monthly blood loss	Normal	Normal (20-80mL)	27 (90)	3 (10)	<0.001
	Abnormal	Heavy (>80mL)	2 (6.7)	2 (6.7)
		Light (<20mL)	0	2 (6.7)
		Complete Amenorrhea	1 (3.3)	23 (76.7)
Return of menses after HSCT	No return of menses		-	23 (76.7)	-
	Return of menses		-	7 (23.3)
Time interval of return of menses after HSCT (months)	<6 months		-	3/7 (42.9)	-
	6-12 months		-	2/7 (28.6)
	>12 months		-	2/4 (50)
	Median (Range)		-	6 (3-18)

HSCT, hematopoietic stem cell transplantation

*Chi-square test has been applied on normal versus abnormal menstrual cycle pattern.

Table 3. Markers of ovarian reserve in the study population.

VARIABLE		CASES (total: 30) n (%)	CONTROLS (total: 30) n (%)	p-VALUE
AMH (ng/dL)	Median (Range)	0.011 (0.01-0.76)	2.0 (0.11-8.11)	<0.001b
	No. of participants with AMH < 1.2ng/dL	30 (100)	6 (20)	<0.001a
AFC	Median (Range)	0 (0-5)	11 (3-19)	<0.001b
	AFC <5	28 (93.3)	1 (3.3)	<0.001c

AMH, anti mullerian hormone; AFC, antral follicle count

a: Chi-Square Test, b: Wilcoxon-Mann-Whitney U Test, c: Fisher’s Exact Test

Successful pregnancy rates and obstetric outcomes in HSCT recipients

Among the cases, 18 women had completed their families. All remaining 12 women who desired future pregnancy were offered oocyte preservation prior to HSCT. Of these, only 3 (25%) women had attempted oocyte preservation prior to HSCT, which was successful in only one patient, who has yet to plan a pregnancy. Among the 12 women who desired pregnancy, seven women had attempted natural conception at the time of the last follow-up. Among these seven women, 2 (28.5%) women had spontaneous conception despite low AMH levels (0.018 and 0.027 ng/mL) and low AFC (1 follicle and two follicles), respectively. While one of these had received a reduced intensity fludarabine-melphalan conditioning for an allogeneic HSCT for myelodysplastic syndrome, the other patient had received a myeloablative BEAM conditioning as a part of autologous transplant consolidation for relapsed Hodgkin lymphoma. The time to natural conception was 7 months and 14 months post-HSCT, respectively, in these two women. The pregnancy was uncomplicated in both patients, and one patient had normal vaginal delivery of an average-weight liveborn girl, while the other underwent caesarean section to deliver a healthy liveborn boy.

Attitudes of women post-HSCT towards acceptance for hormone replacement therapy and its impact on sexual function

All women with premature amenorrhea and an FSH level above 40 IU/dL were offered HRT. Among the patients who were willing, HRT was offered to all women with premature amenorrhea. Approximately 77% (23/30) of women were eligible for HRT at the time of recruitment. Of the remaining, 2/7 were antenatal, 2/7 had regular menses, while the remaining 3/7 had already received HRT and did not want to reinitiate. Of these 23 women, 12/23 (52.2%) refused HRT initiation (Supplementary Figure 1). The common reasons cited for HRT refusal included fear of side effects (50% of women), women felt minimal or no symptoms related to ovarian insufficiency (58.3% of women) and nearing menopause (41.7% of women). Of the remaining, 11/23 (47.8%) were started on HRT. All women underwent FSH level testing prior to initiation of HRT, and all of them had levels above 40 IU/L, confirming the diagnosis of premature ovarian failure as their aetiology of amenorrhea. At 6 months from initiation of HRT, all women were reinterviewed to assess the response to HRT. The majority of women (8/11, 72.7%) reported improvement in genitourinary symptoms, such as vaginal dryness, burning, and irritation. Nine out of 11 (81.8%) reported resumption of menses, three out of 11 (27.3%) reported remission of hot flashes, while two out of 11 (18.2%) did not notice any apparent change. None of the women reported any side effects or episodes of venous thromboembolism during the study period.

Assessment of sexual function in study population and impact of HRT on sexual function

FSFI scores were used to assess the sexual dysfunction at the time of study enrollment and were reassessed at 6 months among women who were administered HRT. Among the sexually active women (n=26), a high frequency of sexual dysfunction was noted, with 24/26 (92.7%) cases having FSFI scores below 26.5, as compared to only 1/30 (3.3%) in controls. All cases had lower scores in all six domains of sexual function as compared to controls (Figure 1, Supplementary Table 2).

Figure 1. Comparison of FSFI score and its components among cases (n=26) and controls (n=30) [Median (Range)].

Test of significance: Mann Whitney U

Among 11 women who were administered HRT, nine were sexually active, with 8 of them (88.9%) experiencing sexual dysfunction (FSFI < 26.5) prior to HRT initiation. At 6 months after HRT initiation, 8 of 9 women showed improvement in the FSFI score, with three women achieving normalization of their FSFI score to above 26.5 (Figure 2, Supplementary Table 3). Overall, there were significant improvements in the arousal, satisfaction and total FSFI components following HRT (Supplementary Table 4).

Figure 2. Comparison of FSFI scores before and after initiation of HRT (n=9).

Discussion

Ovarian insufficiency is the most common gynaecological consequence of HSCT. The current study high rates of premature ovarian failure as evidenced by the lack of menstrual resumption in 66.7% (23/30) of patients. Additionally, AMH levels were below 1.2 ng/mL in all 30 cases (100%), and AFC was less than 5 in 28/30 (93.3%) cases. Also, sexual dysfunction was noted in a majority (92.7%) of women. These findings confirm the cumulative detrimental impact of treatments prior to HSCT and HSCT per se on the reproductive and sexual health of women. Acceptance for fertility-preserving options remained low among HSCT recipients pretransplant (3/12, 25%). Similarly, only 11/23 (47.8%) eligible patients accepted HRT, although most women who received HRT reported improvement in their sexual functions, and 9/11 (81.8%) also resumed their menses. These findings highlight the significant underutilization of strategies that have the potential to partly ameliorate the impact of ovarian dysfunction that develops in HSCT recipients.

Multiple studies have shown gonadal damage in 76-100% of HSCT survivors, and the same was confirmed in the current study^5,11. Even among the minority of patients who resumed menses, the patterns of menstruation showed significant variations as compared to healthy controls. Conventionally, serially elevated FSH levels and low estradiol are used as biochemical markers suggestive of premature ovarian insufficiency in women not on hormonal therapy. AMH is a menstrual cycle-independent marker of ovarian reserve. Both low AFC and AMH levels have been used to predict premature ovarian impairment and menstrual resumption patterns among patients treated with cancer¹². Low AMH levels are associated with premature menopause and are also variably associated with infertility. However, there is scarce data on the AMH level trends in HSCT recipients and their correlation with reproductive and menstrual recovery. In a previous study with a relatively younger cohort of females, median AMH levels were shown to be more sensitive and specific than other markers in evaluating ovarian reserve after HSCT. The study reported decreased AMH levels in 26 of 28 (93%) patients¹³. In the current study, 100% of HSCT recipients had AMH levels below normal (< 1.2 ng/mL) as well as an AFC count below 5; however, AMH levels > 0.01 ng/mL and an AFC > 1 was associated with a higher probability of menstrual resumption post-HSCT. The AMH levels related to fertility have been variably reported, ranging from > 0.6 ng/mL to > 1.06 ng/mL ^14,15. The annual rate of first reported pregnancy in a German cohort post HSCT was 0.53% and it was > 6 times lower than the normal population¹⁶. Non-malignant disease and non-myeloablative/reduced-intensity conditioning were associated with a higher likelihood of motherhood. In the current study, two patients experienced a pregnancy on follow-up, despite low AMH levels (0.02 and 0.027 ng/mL) and low AFC (1 and 2), respectively, of which one had received a myeloablative conditioning. These data suggest that despite the high frequency of ovarian dysfunction post-HSCT, as evidenced by low AMH levels and AFC, spontaneous pregnancies are possible. These findings also support previous observations that single values of AMH or AFC cannot be fully predictive of ovarian failure and need to be corroborated with serial values before decisions regarding future menstrual recovery and fertility potential are made and conveyed to HSCT recipients¹⁷.

Given the curative potential of HSCT in the treatment of hematologic malignancy and high rates of ovarian dysfunction post HSCT, fertility preservation is now recommended as the standard of care in eligible patients planning to undergo HSCT procedures¹⁸. Few studies have reported the impact of fertility preservation procedures on potential delays for lymphoma treatment, although this is not known to impact survival¹⁹. Despite this, only a quarter of patients who were eligible for fertility/oocyte preservation opted for the same in the current study. These findings reflect gaps in the hemato-onco-fertility care and persistent fear regarding delays in the transplant procedures while awaiting fertility preservation procedures among the physicians as well as patients.

HRT initiation in women with premature ovarian insufficiency confers several advantages. These include mitigating the risks of osteoporosis, improving cardiovascular and metabolic health, correcting iron overload after resumption of menses, contraception, and enhancing sexual health. These risks need to be weighed against the risks of thromboembolism, drug interactions, hepatotoxicity and added pill burden associated with HRT use. Limited studies have reported the safety of HRT in women who have undergone HSCT⁸. None of the patients who received HRT experienced any immediate or short-term complications in the current study, indicating the safety of HRT in this subgroup of patients. While 9/11 (81.8%) patients who received HRT resumed menses, all patients who received HRT reported improvement in hot flushes and vaginal symptoms, as well as sexual functions. However, acceptance of HRT among HSCT survivors continues to remain a significant barrier. This was highlighted in the current study by a 47.8% acceptance rate, with the concern for side effects and additional pill burdens as common reasons for HRT refusal.

The physicians often overlook sexual dysfunction despite being experienced by a majority of HSCT patients²⁰. Up to 82% of women reported no discussion regarding this aspect with their healthcare providers, despite more than half being desirous of such a discussion in previous surveys²¹. In the current study, varying degrees of sexual dysfunction were reported in 92.3% cases, affecting all the common domains of sexual function. The mean FSFI score of the population was 16.5±8.8, which is similar to the previous findings reported in autologous transplant survivors of lymphoma²². Majority (8/9) of patients who received HRT appeared to show improvement in sexual function, suggesting the potential role of this intervention in improving sexual health among HSCT recipients.

Although the current study confirms that the majority of HSCT recipients experience ovarian failure, a significant limitation of the study is its small sample size, retrospective collection of pre-HSCT details, and limited follow-up, which may have led to potential selection and information bias inherent to the study design. The markers of ovarian reserve prior to transplantation were not available, making it difficult to precisely estimate the impact of HSCT on ovarian reserve in relation to the pre-transplantation gonadotoxic effects of chemoradiotherapy. Moreover, given the cross-sectional nature of the study, AFC and AMH levels were analysed only once, rather than serially, and the patients recruited were at varying intervals following HSCT. Despite these limitations, the study highlights the need for future research to identify barriers in the provision of optimal peri-transplant fertility care, as well as the development of ovarian function preservation strategies before and after HSCT.

Conclusion

In this small cross-sectional study that explored ovarian and sexual function in women who underwent HSCT, a majority of patients experienced ovarian failure and sexual dysfunction following HSCT, with spontaneous resumption only in a few. HRT initiation post-HSCT improves sexual dysfunction but has low rates of acceptance among HSCT survivors.

Conflicts of Interest

The authors declare no conflict of interest. Disclosure forms provided by the authors are available on the website. DL is one of the editors of Blood Cell Therapy. He was not involved in the editorial evaluation or decision to accept this article for publication.

Author Contributions

RJ and AA have equally contributed to the manuscript. RJ, AA, and AJain contributed to the literature search, manuscript writing and data analysis. DL, AA, and AM conceptualized the initial study design. AJandial, CS, AK, GP, PM, and VJ helped in recruiting patients. RD helped in hematological diagnostic workup. All authors contributed suggestions and verified the final manuscript.