# Is there a relationship between tumour aggressiveness and ovarian stimulation outcomes in adolescent and young adult patients with lymphoma?

Virginie Simon, C. Chuzel, H. Behal, J. Labreuche, Salomon Manier, Franck

Morschhauser, P. Pigny, L. Keller, M. Nudel, C. Decanter

► To cite this version:

Virginie Simon, C. Chuzel, H. Behal, J. Labreuche, Salomon Manier, et al.. Is there a relationship between tumour aggressiveness and ovarian stimulation outcomes in adolescent and young adult patients with lymphoma?. Reproductive BioMedicine Online, 2025, Reproductive BioMedicine Online, 50 (3), pp.104448. 10.1016/j.rbmo.2024.104448. hal-05096513

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ARTICLE

# Is there a relationship between tumour aggressiveness and ovarian stimulation outcomes in adolescent and young adult patients with lymphoma?

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<figure><img src="image_2.png" /></figure>

## BIOGRAPHY

Virginie Simon is a gynaecologist, sub-specializing in reproductive medicine. She works at Jeanne de Flandre, Lille (France) in the Department of Assisted Reproductive Technologies and Fertility Preservation.

V. Simon<sup>1,2,*</sup>, C. Chuzel<sup>3</sup>, H. Behal<sup>4</sup>, J. Labreuche<sup>4</sup>, S. Manier<sup>3,5</sup>, F. Morschhauser<sup>2,3</sup>, P. Pigny<sup>2,6,7</sup>, L. Keller<sup>8</sup>, M. Nudel<sup>2,3</sup>, C. Decanter<sup>1,5</sup>

## KEY MESSAGE

Tumour aggressiveness does not appear to influence the number of metaphase II oocytes retrieved in young patients with Hodgkin lymphoma. These results suggest that fertility preservation should be proposed systematically, regardless of the stage of Hodgkin disease, in young women. No serious adverse events were observed, suggesting that fertility preservation procedures are safe in this population.

## ABSTRACT

**Research question:** Does the aggressiveness of Hodgkin lymphoma impact the oocyte cohort after ovarian stimulation for fertility preservation?

**Design:** A retrospective analysis of prospectively collected data was undertaken. Seventy-seven chemo-naive women with newly diagnosed Hodgkin lymphoma were enrolled prospectively at the Observatory and Fertility Preservation Centre, Lille University Hospital, France between 2012 and 2021. Seventy-eight ovarian stimulation cycles were performed. Oocyte cohort characteristics were compared between patients with early and intermediate stage disease [German Hodgkin Study Group (GHSG) I + II] and patients with advanced stage disease (GHSG III). Among the GHSG III patients, the influence of the Hasenclever score on fertility preservation outcomes was analysed. The primary endpoint was the number of metaphase II oocytes (MII) retrieved.

**Results:** The groups were comparable except for body mass index (BMI). Overall, a median of seven (interquartile range 4–11) MII oocytes were retrieved. Before and after adjustment for BMI, age, pre-treatment anti-Müllerian hormone concentration, and total dose of gonadotrophin, GHSG status did not have a significant impact on the number of MII oocytes retrieved [relative risk 0.96, 95% confidence interval 0.68–1.34; *P* = 0.79] or the other ovarian stimulation outcomes. The Hasenclever score was not significantly associated with the number of MII oocytes retrieved.

## KEY WORDS

Hodgkin lymphoma

Fertility preservation

Oocyte cryopreservation

Follicles

Ovarian stimulation

Adolescent and young adult

<footnote n="1">¹ Department of Assisted Reproductive Technologies and Fertility Preservation, Jeanne de Flandre Hospital, Lille, France</footnote>

<footnote n="2">² Faculty of Medicine, University of Lille, Lille, France</footnote>

<footnote n="3">³ Department of Haematology, CHU Lille, Lille, France</footnote>

<footnote n="4">⁴ Department of Biostatistics, CHU Lille, Lille, France</footnote>

<footnote n="5">⁵ OncoLille, Canther, INSERM UMR-S1277, CNRS UMR9020, Lille University, Lille, France</footnote>

<footnote n="6">⁶ Department of Biochemistry and Hormonology, CHU Lille, Lille, France</footnote>

<footnote n="7">⁷ University of Lille, INSERM, UMR-S 1277, Lille, France</footnote>

<footnote n="8">⁸ Department of Reproductive Biology–Spermiology–CECOS, Jeanne de Flandre Hospital, CHU Lille, Lille, France</footnote>
**Conclusion:** Tumour aggressiveness was not found to have a significant influence on the number of MII oocytes retrieved in young women with Hodgkin lymphoma. These results suggest that fertility preservation should be proposed systematically, regardless of the stage of Hodgkin disease, in young women.

## INTRODUCTION

Hodgkin lymphoma is one of the most common malignant diseases in young adults (Miller et al., 2020). The overall survival rate of these young patients has increased significantly over recent decades due to new therapeutic protocols (Ohbiki et al., 2023), and healthcare professionals work to improve the quality of life of these patients during and after cancer treatment. Fertility is a key consideration in quality-of-life assessment, and one of the major concerns for these young patients (Letourneau et al., 2012). The impact of chemotherapy on ovarian function and subsequent fertility differs according to the type of chemotherapy. The degree of toxicity of chemotherapy also depends on the age of the patient at the initiation of treatment and the pre-treatment anti-Müllerian hormone (AMH) concentration (Anderson et al., 2013; Dillon et al., 2013). Chemotherapy including alkylating or alkylating-like agents is toxic to follicles, regardless of their stage of development (primordial to antral stage) (Spears et al., 2019).

In patients with lymphoma, the recovery of ovarian function (represented by a re-increase in AMH concentration and return of menses) differs according to the presence or absence of alkylating agents (Anderson et al., 2018; Behringer et al., 2013; Decanter et al., 2010; Su et al., 2020). Recent studies confirmed that alkylating protocols used for lymphoma treatment have strong ovarian toxicity regardless of the cumulative dose, even in adolescent and young adult (AYA) patients. These patients exhibit limited recovery of AMH concentration after the end of treatment (Anderson et al., 2022; Decanter et al., 2021; Su et al., 2020), suggesting a significant loss of follicles.

According to the recommendations of the American Society of Clinical Oncology, the European Society for Medical Oncology, and the European Society of Human Reproduction and Embryology, all patients undergoing gonadotoxic treatment should be referred to an oncofertility centre for counselling on the impact of the disease, the potential impact of cytotoxic treatment on ovarian reserve, and available fertility preservation methods (ESHRE Guideline

Group on Female Fertility Preservation et al., 2020; Lambertini et al., 2020; Mulder et al., 2021; Oktay et al., 2018;).

Studies investigating the ovarian response to ovarian stimulation in patients with cancer have shown discordant results. Some studies reported a higher incidence of low ovarian response, with a suboptimal number of oocytes retrieved under ovarian stimulation for fertility preservation in patients with cancer (Decanter et al., 2018; Domingo et al., 2012; Friedler et al., 2012; Lawrenz et al., 2012; Sonigo et al., 2018), whereas others showed no difference (Brun et al., 2021; Turan et al., 2018; von Wolff et al., 2018).

Finally, two meta-analyses evaluated the impact of a cancer diagnosis on response to ovarian stimulation. One (Turan et al., 2018) did not find any difference in the number of MII oocytes between patients with and without cancer. However, patients with haematological malignancies accounted for only 12% of the total sample. The other meta-analysis (Friedler et al., 2012) showed a significantly decreased number of MII oocytes in patients with cancer.

In all of these studies, most of which were retrospective, the response to controlled ovarian hyperstimulation (COH) was evaluated according to the type of cancer, but not according to its aggressiveness. Furthermore, specific data on patients with lymphoma are scarce in the literature and often retrospective.

However, this topic is clinically important when planning fertility preservation by oocyte vitrification, because it helps to determine how to adjust the initial dose of gonadotrophin for ovarian stimulation. This study aimed to investigate the pattern of follicular growth and the oocyte cohort under COH in young patients with lymphoma for fertility preservation according to tumour aggressiveness and inflammatory-specific indicators.

## MATERIALS AND METHODS

### Study design

This observational, single-centre cohort study reviewed the outcomes for patients

with Hodgkin lymphoma who received ovarian stimulation treatment for oocyte cryopreservation before chemotherapy between 2012 and 2021. A retrospective analysis of data collected prospectively in the prospective oncofertility database was undertaken.

All patients had given prior consent for data analysis. On 16 December 2019, the Institutional Review Board of Lille University Hospital gave unrestricted approval for the anonymous use of all patients' clinical, hormonal and ultrasound records (Reference DEC20150715-0002).

### Population

In total, 77 women aged 16–35 years with a diagnosis of Hodgkin lymphoma were recruited prospectively between 2012 and 2021 at the Fertility Preservation Centre, Lille University Hospital. All were chemotherapy-naive at the time of inclusion. None of the patients had undergone ovarian tissue cryopreservation or other ovarian surgery. The hospital and all patients provided informed consent (DC-2008-642; CNIL DEC2015112). This study is part of the project 'Elle va guérir puis voudra un enfant', funded by the 'Hauts de France' cancer and health agencies.

Hodgkin lymphoma was diagnosed by lymph node biopsy according to the criteria of the World Health Organization, and confirmed by an expert anatomopathologist. At diagnosis, blood samples and a positron emission tomography scan were performed to assess the stage of disease according to the criteria of the German Hodgkin Study Group (GHSG), and to determine the optimal treatment. GHSG status distinguishes three stages of Hodgkin lymphoma – early, intermediate and advanced – using Ann Arbor staging and four risk factors (number of lymph nodes, bulk mass, erythrocyte sedimentation rate, and extranodal involvement). The study population was divided into two groups according to GHSG status (early and intermediate Hodgkin lymphoma versus advanced Hodgkin lymphoma). The Hasenclever score was calculated for patients with advanced Hodgkin lymphoma. This score is based on seven factors: age; sex; serum albumin;
haemoglobin concentration; Ann Arbor stage; leukocytosis; and lymphocytopenia. The score is defined as the number of adverse prognostic factors present at diagnosis, and predicts the 5-year progression-free survival rate in patients with advanced Hodgkin lymphoma. With each additional factor, the predicted rate is reduced by approximately 8% (Eichenauer et al., 2018; Hasenclever and Diehl, 1998).

## Study protocol

### Fertility assessment

Patients were referred to the Fertility Observatory of Lille University Hospital before the initiation of chemotherapy for follow-up regarding menstrual activity and ovarian follicular content through serial blood AMH measurements.

The fertility assessment included: medical history and lifestyle; calculation of BMI; AMH assay; and ultrasound examination for evaluation of ovarian reserve by counting the antral follicles (2–9 mm diameter). The ultrasound examination was performed using a Voluson E8 Expert ultrasound machine with an endovaginal probe at 5–9 MHz (General Electric Systems, France) according to the real-time two-dimensional procedure (Coelho Neto 2018). AMH concentration was measured using a second-generation AMH enzyme immunoassay kit (A16507; Beckman Coulter Immunotech, France).

### Ovarian stimulation and oocyte retrieval

All patients received an antagonist protocol. Daily subcutaneous injections of recombinant FSH (r-FSH) or human menopausal gonadotrophin were administered. The r-FSH starting dose was determined based on age, BMI, antral follicle count and AMH concentration.

Patients were monitored on day 6 of FSH treatment and every 2–3 days until the follicles reached the size required for oocyte release. Ovulation was triggered by a subcutaneous injection of 250 µg of recombinant human chorionic gonadotrophin (Ovitrelle; Merck Serono, France) and/or 0.2 mg of a short half-life gonadotrophin-releasing hormone (GnRH) agonist (triptorelin 0.2 mg) when at least three follicles reached 17 or 18 mm. Thirty-six hours after this injection, transvaginal ultrasound-guided oocyte retrieval was performed.

Metaphase II (MII), metaphase I and germinal vesicle oocytes were vitrified.

Immature oocytes were vitrified for later in-vitro maturation at the time of use. The protocol for oocyte vitrification was described previously (Decanter et al., 2018).

Any serious adverse events during ovarian stimulation, and during and after oocyte retrieval were reported.

### Statistical analysis

Categorical variables have been expressed as frequency and percentage, and continuous variables have been expressed as mean ± SD or median and interquartile range (IQR). The normality of the distribution was checked graphically and using the Shapiro-Wilk test.

For the primary objective, all candidate factors were introduced into a multivariable regression model from the outset. The model depended on the nature of the outcome: a generalized estimating equation (GEE) model with negative binomial distribution and logit link function was used for the number of follicles >15 mm diameter, the number of oocytes retrieved, the number of MII oocytes retrieved, and the maturation rate (ratio of MII oocytes/total oocytes), considering the number of MII oocytes as the dependent variable and the number of oocytes retrieved after log-transformation as the offset. A linear regression model was used for oestradiol on the trigger day, and the ratio of metaphase II oocytes/follicles >15 mm diameter. Relative risks (RR) and 95% confidence intervals (CI) were expressed as effect sizes from the GEE model; linear regression coefficients (β) and 95% CI were expressed as effect sizes from the linear regression model. Concentrations of AMH and oestradiol on the trigger day were analysed after log-transformation.

The influence of GHSG status, considered as a binary variable (GHSG I + II versus GHSG III), on the fertility outcome parameters was assessed with and without adjustment for confounding factors such as AMH concentration, BMI, age, and total dose of gonadotrophin. The same models as described for the primary objective were used.

Spearman's correlation coefficient (ρ) was used to assess the relationship between the Hasenclever score and the fertility outcome parameters in the subgroup of patients with advanced Hodgkin lymphoma.

Data were analysed using SAS (SAS Institute, USA), and all statistical tests were performed with a two-tailed alpha risk of 0.05.

## RESULTS

In total, 77 patients with Hodgkin lymphoma, undergoing 78 ovarian stimulation cycles, were included in this study. Only one patient underwent two ovarian stimulation cycles.

Patient characteristics are reported in **TABLE 1**. The mean ± SD age was 23.4 ± 4.5 years, and the mean ± SD BMI was 23.3 ± 4.4 kg/m². The median blood concentration of AMH was 17.1 (IQR 9.0–25.5) pmol/ml. No significant differences were found between the GHSG III and GHSG I + II groups, except for BMI, which was lower in the GHSG III group (22.4 ± 3.5 versus 25.1 ± 5.4 kg/m²; *P* = 0.029), and the presence of B symptoms (i.e. fever, night sweats and unintentional weight loss), which were significantly more frequent in the GHSG III group (67.9% versus 20.8%; *P* < 0.001).

The characteristics of ovarian stimulation cycles are reported in **TABLE 2**. The median duration of stimulation was 11 (IQR 10–12) days. No serious adverse events occurred.

### Influence of age, BMI, total dose of gonadotrophin, and AMH concentration on ovarian response

Analysis of ovarian response in a multivariable model including age, BMI, total dose of gonadotrophin, and log-transformed AMH concentration revealed that AMH concentration alone was significantly associated with the number of MII oocytes retrieved (RR 1-log AMH increase 1.68, 95% CI 1.22–2.31; *P* = 0.002) (Supplementary Table 1). AMH concentration and age were significantly associated with oestradiol concentration on the trigger day (β 1-log AMH increase 0.49, 95% CI 0.20–0.77, *P* = 0.001; β 4-year increase 0.15, 95% CI 0.006–0.29; *P* = 0.041, respectively). The total dose of gonadotrophin did not reach significance (*P* = 0.080) considering the oestradiol concentration on the trigger day. AMH concentration and the total dose of gonadotrophin were significantly associated with the number of follicles >15 mm diameter (RR 1-log AMH increase 1.33, 95% CI 1.08–1.65, *P* = 0.007; RR
<table><caption>TABLE 1 PATIENT CHARACTERISTICS</caption><thead><tr><th>Characteristic</th><th>Overall population (n = 78)<sup>a</sup></th><th>GHSG I + II (n = 25)<sup>b</sup></th><th>GHSG III (n = 53)</th><th>P-value</th></tr></thead><tbody><tr><td>Age (years), mean ± SD</td><td>23.4 ± 4.5</td><td>24.6 ± 5.7</td><td>22.8 ± 3.7</td><td>0.17<sup>d</sup></td></tr><tr><td>BMI (kg/m<sup>2</sup>), mean ± SD<sup>f</sup></td><td>23.3 ± 4.4</td><td>25.1 ± 5.4</td><td>22.4 ± 3.5</td><td>0.029<sup>d</sup></td></tr><tr><td>Smoking</td><td>20/58 (34.5)</td><td>5/23 (21.7)</td><td>15/35 (42.9)</td><td>0.098<sup>e</sup></td></tr><tr><td>OCP use at diagnosis</td><td>34/78 (43.6)</td><td>10/25 (40.0)</td><td>24/53 (45.3)</td><td>0.66<sup>e</sup></td></tr><tr><td>AMH (pmol/l), median (IQR)<sup>g</sup></td><td>17.1 (9.0–25.5)</td><td>19.9 (12.7–30.3)</td><td>15.2 (8.4–21.1)</td><td>0.11<sup>f</sup></td></tr><tr><td>AFC, mean ± SD<sup>k</sup></td><td>23.0 ± 11.1</td><td>22.4 ± 11.6</td><td>23.3 ± 10.9</td><td>0.75<sup>d</sup></td></tr><tr><td>Performance status</td><td></td><td></td><td></td><td>0.96<sup>e</sup></td></tr><tr><td>0</td><td>44/78 (56.4)</td><td>14/25 (56.0)</td><td>30/53 (56.6)</td><td></td></tr><tr><td>1</td><td>34/78 (43.6)</td><td>11/25 (44.0)</td><td>23/53 (43.4)</td><td></td></tr><tr><td>2</td><td>0</td><td>0</td><td>0</td><td></td></tr><tr><td>3</td><td>0</td><td>0</td><td>0</td><td></td></tr><tr><td>4</td><td>0</td><td>0</td><td>0</td><td></td></tr><tr><td>Histology, scleronodular</td><td>66/76 (86.8)</td><td>21/24 (87.5)</td><td>45/52 (86.5)</td><td>1.00<sup>k</sup></td></tr><tr><td>Presence of B symptoms</td><td>41/77 (53.2)</td><td>5/24 (20.8)</td><td>36/53 (67.9)</td><td>&lt;0.001<sup>e</sup></td></tr><tr><td>Ann Arbor stage</td><td></td><td></td><td></td><td>NA</td></tr><tr><td>I</td><td>4/78 (5.1)</td><td>4/25 (16.0)</td><td>0/53 (0.0)</td><td></td></tr><tr><td>II</td><td>29/78 (37.2)</td><td>21/25 (84.0)</td><td>8/53 (15.1)</td><td></td></tr><tr><td>III</td><td>26/78 (33.3)</td><td>0 (0.0)</td><td>26/53 (49.1)</td><td></td></tr><tr><td>IV</td><td>19/78 (24.4)</td><td>0 (0.0)</td><td>19/53 (35.8)</td><td></td></tr><tr><td>Hasenclever score<sup>c</sup></td><td>NA</td><td>NA</td><td>NA</td><td>NA</td></tr><tr><td>0</td><td></td><td></td><td>9/40 (22.5)</td><td></td></tr><tr><td>1</td><td></td><td></td><td>12/40 (30.0)</td><td></td></tr><tr><td>2</td><td></td><td></td><td>12/40 (30.0)</td><td></td></tr><tr><td>3</td><td></td><td></td><td>4/40 (10.0)</td><td></td></tr><tr><td>4</td><td></td><td></td><td>2/40 (5.0)</td><td></td></tr><tr><td>5</td><td></td><td></td><td>1/40 (2.5)</td><td></td></tr><tr><td>6</td><td></td><td></td><td>0</td><td></td></tr><tr><td>7</td><td></td><td></td><td>0</td><td></td></tr><tr><td>CRP (mg/l), median (IQR)<sup>l</sup></td><td>38 (13–68)</td><td>28 (7–40)</td><td>47 (13–82)</td><td>0.096<sup>h</sup></td></tr></tbody></table>

1000 IU increase 0.87, 95% CI 0.76–0.99, P = 0.042, respectively), and the total number of oocytes retrieved (RR 1-log AMH increase 1.48, 95% CI 1.12–1.95, P = 0.005; RR 1000 IU increase 0.80, 95% CI 0.67–0.95, P = 0.012, respectively). The relationship between BMI and the number

of follicles >15 mm diameter was not significant (RR 4 kg/m² increase 1.10, 95% CI 0.99–1.22; P = 0.057).

Age, BMI, total dose of gonadotrophin, and AMH concentration were not significantly associated with maturation rate or the ratio

of MII oocytes/follicles >15 mm diameter (Supplementary Table 2).

## Influence of lymphoma characteristics on ovarian response

Overall, the median total number of oocytes retrieved was 10 (IQR 5–17), with a

<footnote><sup>a</sup>Seventy-eight ovarian stimulation cycles were performed in 77 patients; the one patient who underwent two cycles was GHSG I. All data are described per cycle.</footnote>

<footnote><sup>b</sup>GHSG I n = 8, GHSG II n = 17.</footnote>

<footnote><sup>c</sup>Hasenclever score was only available for 40 patients.</footnote>

<footnote><sup>d</sup>Student's t-test.</footnote>

<footnote><sup>e</sup>Chi-squared test.</footnote>

<footnote><sup>f</sup>Mann-Whitney U-test.</footnote>

<footnote><sup>g</sup>Fisher's exact test.</footnote>

<footnote><sup>h</sup>Student's t-test on log-transformed CRP values.</footnote>

<footnote><sup>i</sup>Four missing data in overall population: all in GHSG III.</footnote>

<footnote><sup>j</sup>One missing data in overall population: in GHSG I + II.</footnote>

<footnote><sup>k</sup>Three missing data in overall population: all in GHSG III.</footnote>

<footnote><sup>l</sup>Nine missing data in overall population: three in GHSG I + II, six in GHSG III.</footnote>

<footnote>GHSG, German Hodgkin Study Group; BMI, body mass index; OCP, oral contraception pill; IQR, interquartile range; AFC, antral follicle count; CRP, C reactive protein; NA, not applicable.</footnote>
<table><caption>TABLE 2 CHARACTERISTICS OF OVARIAN STIMULATION CYCLES</caption><thead><tr><th>Parameter</th><th>Overall population<br>n = 78 cycles</th><th>GHSG I + II<br>n = 25</th><th>GHSG III<br>n = 53</th><th>P-value</th></tr></thead><tbody><tr><td>Time interval between diagnosis and oocyte retrieval (days), median (IQR)<sup>c</sup></td><td>35 (23–49)</td><td>34 (27–43)</td><td>36 (21–50)</td><td>1.00<sup>a</sup></td></tr><tr><td>Starting dose of gonadotrophin (IU), median (IQR)<sup>d</sup></td><td>269 (225–300)</td><td>300 (225–300)</td><td>262.5 (225–300)</td><td>0.68<sup>a</sup></td></tr><tr><td>Duration of stimulation (days), median (IQR)<sup>d</sup></td><td>11 (10–12)</td><td>11.0 (10–11)</td><td>11.0 (10–13)</td><td>0.18<sup>a</sup></td></tr><tr><td>Total gonadotrophin dose (IU), median (IQR)<sup>d</sup></td><td>2988 (2250–3675)</td><td>2800 (2325–3300)</td><td>3050 (2250–3950)</td><td>0.34<sup>a</sup></td></tr><tr><td>Trigger mode</td><td></td><td></td><td></td><td>0.60<sup>b</sup></td></tr><tr><td>GnRH + HCG</td><td>26/72 (36.1)</td><td>9/24 (37.5)</td><td>17/48 (35.4)</td><td></td></tr><tr><td>GnRH</td><td>17/72 (23.6)</td><td>4/24 (16.7)</td><td>13/48 (27.1)</td><td></td></tr><tr><td>HCG</td><td>29/72 (40.3)</td><td>11/24 (45.8)</td><td>18/48 (37.5)</td><td></td></tr></tbody></table>

median of seven (IQR 4–11) MII oocytes retrieved. Outcomes of ovarian stimulation cycles according to GHSG group are presented in **TABLE 3**. No significant relationship was found between GHSG group and the number of MII oocytes retrieved (RR 0.82, 95% CI 0.56–1.19; *P* = 0.30, *P* adjusted = 0.79). Similarly, oestradiol on the trigger day, number of follicles >15 mm diameter, number of oocytes retrieved, maturation rate, and the ratio of MII oocytes/follicles >15 mm diameter were not affected significantly by GHSG group.

Finally, of the 53 patients with advanced Hodgkin lymphoma, only 40 had data available to determine the Hasenclever international prognostic score (IPS). Nine patients had a score of 0, four patients had a score of 3, and two patients had a score of 4. IPS of 1 (n = 12, 30%) and 2 (n = 12, 30%) were most common. As two factors of the Hasenclever index were not represented in the study cohort (age >45 years and male sex), the highest IPS was 5 (n = 1).

No significant correlation was found between IPS and the number of MII oocytes retrieved, despite a negative association with the oestradiol concentration on the trigger day (*ρ* = -0.36, 95% CI -0.61 to -0.02; *P* = 0.034) and the number of follicles >15 mm diameter (*ρ* = -0.44, 95% CI -0.70 to -0.14).

<table><caption>TABLE 3 OUTCOMES OF OVARIAN STIMULATION CYCLES ACCORDING TO GERMAN HODGKIN STUDY GROUP</caption><thead><tr><th rowspan="2">Parameter</th><th rowspan="2">GHSG I + II<br>n = 25</th><th rowspan="2">GHSG III<br>n = 53</th><th colspan="3">GHSG III versus GHSG I + II (reference)</th></tr><tr><th>Without<br>adjustment</th><th>P-value</th><th>With<br>adjustment<sup>d</sup></th><th>P-value</th></tr></thead><tbody><tr><td>Oestradiol at trigger day, median (IQR)<sup>a</sup></td><td>2017<br>(1602–3185)</td><td>1324<br>(815–2306)</td><td>β (95% CI)</td><td>-0.34 (-0.73 to 0.04)</td><td>0.07<sup>a</sup></td><td>-0.06 (-0.04 to 0.28)</td><td>0.73<sup>a</sup></td></tr><tr><td>Follicles >15 mm diameter, median (IQR)<sup>a</sup></td><td>8 (7–13)</td><td>9 (6–12)</td><td>RR (95% CI)</td><td>0.92 (0.70–1.20)</td><td>0.54<sup>b</sup></td><td>0.88 (0.69–1.12)</td><td>0.31<sup>b</sup></td></tr><tr><td>MII oocytes, median (IQR)<sup>f</sup></td><td>9 (4–13)</td><td>6 (3–10)</td><td>RR (95% CI)</td><td>0.82 (0.56–1.19)</td><td>0.30<sup>b</sup></td><td>0.96 (0.68–1.34)</td><td>0.79<sup>b</sup></td></tr><tr><td>Oocytes retrieved, median (IQR)<sup>g</sup></td><td>12 (8–17)</td><td>9 (5–15)</td><td>RR (95% CI)</td><td>0.84 (0.59–1.18)</td><td>0.31<sup>b</sup></td><td>0.92 (0.67–1.24)</td><td>0.57<sup>b</sup></td></tr><tr><td>Maturation rate, %<sup>f,g</sup></td><td>72.0</td><td>69.1</td><td>RR (95% CI)</td><td>0.99 (0.83–1.17)</td><td>0.88<sup>c</sup></td><td>0.99 (0.81–1.19)</td><td>0.88<sup>c</sup></td></tr><tr><td>MII oocytes/follicles >15 mm diameter,<br>median (IQR)<sup>h</sup></td><td>0.87 (0.57–1.13)</td><td>0.71<br>(0.36–1.14)</td><td>β (95% CI)</td><td>-0.28 (-0.60 to 0.03)</td><td>0.07<sup>a</sup></td><td>-0.21 (-0.55 to 0.13)</td><td>0.21<sup>a</sup></td></tr></tbody></table>

<footnote>a Mann–Whitney U-test.</footnote>

<footnote>b Chi-squared test.</footnote>

<footnote>c Eight missing data in total population: two in GHSG I + II, six in GHSG III.</footnote>

<footnote>d Two missing data in total population: all in GHSG III.</footnote>

<footnote>GHSG, German Hodgkin Study Group; IQR, interquartile range; GnRH, gonadotrophin-releasing hormone; HCG, human chorionic gonadotrophin.</footnote>

<footnote>a Linear regression model.</footnote>

<footnote>b Generalized estimating equation model with negative binomial distribution.</footnote>

<footnote>c Generalized estimating equation model with negative binomial distribution considering the number of oocytes retrieved after log-transformation as the offset.</footnote>

<footnote>d Adjustment for AMH, BMI, age and total dose of gonadotrophin.</footnote>

<footnote>e Four missing data in overall population: all in GHSG III.</footnote>

<footnote>f Data from 74 cycles (25 cycles in GHSG I + II, 49 cycles in GHSG III) with at least one oocyte retrieved.</footnote>

<footnote>g Two missing data on the number of oocytes retrieved (for these two cycles, the number of MII oocytes was available).</footnote>

<footnote>h Data from 71 cycles with at least one follicle >15 mm diameter.</footnote>

<footnote>GHSG, German Hodgkin Study Group; IQR, interquartile range; MII, metaphase II; RR, relative risk; CI, confidence interval.</footnote>
-0.65 to -0.09; *P* = 0.010) (Supplementary Table 3). In addition, no significant correlation was found between the IPS and the total number of oocytes retrieved, the maturation rate, and the ratio of MII oocytes/follicles >15 mm diameter.

DISCUSSION

Before and after adjustment for BMI, age, AMH concentration and total dose of gonadotrophin, GHSG status did not significantly affect the number of MII oocytes retrieved or other ovarian stimulation outcomes. Among GHSG III patients, the Hasenclever score, which represents the most advanced stage of the disease, was not significantly associated with the number of MII oocytes retrieved. However, this score was only available for a small sample of patients.

The study groups were comparable except for BMI and the presence of B symptoms, which were lower and more frequent in the GHSG III group, respectively. No significant difference in AMH concentration was found between the two GHSG groups. In patients with lymphoma (Hodgkin and non-Hodgkin), a lower AMH concentration before treatment has been described (Lawrenz et al., 2012; Lekovich et al., 2016; Paradisi et al., 2016) in comparison with healthy patients. It remains unclear whether a lower AMH concentration may indicate a decreased ovarian reserve and predict a poorer ovarian response in these patients. A substantial proportion of young patients with lymphoma use an oral contraceptive pill, and this has been shown to decrease granulosa cell production of AMH (Nelson et al., 2023). In the study population, 34 patients (43%) were using hormonal contraception before ovarian stimulation.

Pathophysiological hypotheses have been put forward to explain the lower AMH concentration in patients with lymphoma compared with healthy patients, such as impairment of the hypothalamic–pituitary axis or the elevation of cytokine concentrations, particularly interleukin 6, interleukin 8 and tumour necrosis factor-alpha, which are involved in angiogenesis, follicular development and steroidogenesis (Paradisi et al., 2016). Paradisi et al. showed that the AMH concentration was significantly lower in patients with lymphoma, but did not differ significantly with lymphoma stage (Ann Arbor stage). The present authors also showed a strong

negative correlation between AMH and cytokine concentrations, with the latter being well known to be elevated in lymphoma pathology and to play a key role in the pathogenesis of lymphoma. Fabbri et al. (2011) highlighted significant damage to gametes in women with Hodgkin lymphoma, with a high frequency of follicular damage, such as vacuolization, and a reduced number of viable follicles before chemotherapy. The presence of B symptoms is associated with more advanced disease, and some studies have shown a correlation between cytokine concentrations and the presence of these symptoms (Paradisi et al., 2016).

Due to inflammation, weight loss, fever and changes in general condition, the follicular microenvironment and oocyte quality may differ in young women with Hodgkin lymphoma. MicroRNA have been shown to play a role in ovarian function in patients with Hodgkin lymphoma (Caponnetto et al., 2021). Indeed, some authors found that 13 miRNA were deregulated in women with Hodgkin lymphoma compared with young women without Hodgkin lymphoma (Caponnetto et al., 2021). Likewise, follicular fluid miRNA profiles have been associated with the outcome of IVF cycles and with reproductive disorders affecting oocyte quality in humans and animal models (Machtinger et al., 2017; Martinez et al., 2018; Scalici et al., 2016). This evidence supports the hypothesis that follicular fluid miRNA may represent molecular markers of oocyte quality.

In the current study, GHSG III status was not associated with a lower number of MII oocytes in comparison with GHSG I + II status. Furthermore, among patients with advanced Hodgkin lymphoma, regarding the primary endpoint, no significant association was found between IPS and the number of MII oocytes retrieved. However, a significant association was found between IPS and the oestradiol concentration on the trigger day and the number of follicles >15 mm diameter, showing both a lower ovarian response to COH and lower granulosa cell performance when lymphoma is more aggressive.

A study comparing low- and high-grade cancers found a significantly lower number of MII vitrified oocytes in high-grade cancers (Volodarsky-Perel et al., 2020), highlighting a negative effect of tumour aggressiveness on the results of ovarian stimulation. However, in this study,

cancers were not differentiated according to their type (haematological malignancies, breast cancer, brain tumours). Almog et al. (2012) compared the effect of cancer on ovarian response to stimulation with healthy matched controls, and found no differences between the two groups. However, only 12 of 81 patients had haematological malignancies. A lower maximal oestradiol concentration was found in the study group compared with the control group, which has been shown in other studies (Decanter et al., 2018; Sonigo et al., 2018; Volodarsky-Perel et al., 2020), but with several confounding factors such as letrozole use, various ovarian stimulation protocols, and r-FSH dose (Friedler et al., 2012).

Previously, the authors showed that, despite a higher r-FSH cumulative dose in patients with cancer and the same number of growing follicles, the mean ± SD oestradiol concentration on the trigger day was significantly lower in patients with cancer compared with patients without cancer, with a peak at 1618 ± 1336 pg/ml (*P* < 0.001) (Decanter et al., 2018). This result may represent an early sign of a possible negative effect of cancer on the health of granulosa cells. In the current study, the oestradiol concentration on the trigger day was significantly associated with pre-treatment AMH concentration and age.

In this study, patients with cancer were not compared with healthy controls, but it seems that advanced stage disease may have an impact on oocyte maturity. Indeed, the ratio of MII oocytes/follicles >15 mm diameter appeared to be lower in the GHSG III group compared with the GHSG I + GHSG II group, but this difference did not reach significance (-0.28, 95% CI -0.60 to 0.03; *P* = 0.074). Considering factors that could impact oocyte maturity, no associations were found between oocyte maturity and age, BMI, total dose of gonadotrophin and AMH concentration in any of the study patients. Indeed, even if the AMH concentration was strongly associated with the number of MII oocytes (RR 1.68, 95% CI 1.22–2.31; *P* = 0.002), it was not associated with the ratio of MII oocytes/follicles >15 mm diameter (β 0.28, 95% CI -0.31 to 0.86; *P* = 0.35). It remains unclear whether malignancies may affect oocyte maturation. Pal et al. (1998) were the first to report poorer quality and a significantly reduced percentage of MII oocytes in these patients in a case series of eight cycles of IVF in five women diagnosed with
malignant disorders. In a previous study by the present authors (Decanter et al., 2018), the maturation rate (i.e. ratio of MII oocytes/total oocytes) was significantly lower in the cancer group (56% ± 27% versus 78% ± 16%; P < 0.0001). However, the use of an GnRH agonist trigger may have contributed to this suboptimal result, due to functional impairment of the hypothalamo–pituitary axis in patients with extensive cancer. On the contrary, Das et al. (2011) found no effect of malignancy on the number of oocytes retrieved and oocyte maturity. Alvarez and Ramathan (2018) showed a significant difference in the number of MII oocytes retrieved; fewer MII oocytes were retrieved for patients with gynaecological cancer compared with patients with haematological cancer or breast cancer, but this may have been influenced by the fact that the patients with haematological cancer were significantly younger. Sonigo et al. (2018) found a significantly lower follicular output rate in patients with Hodgkin lymphoma compared with patients with breast cancer, which may suggest that Hodgkin status could alter follicular responsiveness to exogenous FSH. They also found a similar number of MII oocytes in the two groups, despite a higher antral follicle count at baseline and younger age in the patients with Hodgkin lymphoma.

To the authors' knowledge, this is the first series to investigate lymphoma characteristics and aggressiveness indicators and outcomes of ovarian stimulation for fertility preservation in patients with Hodgkin lymphoma. This is the first study to use a standardized prognostic score to evaluate the impact of Hodgkin lymphoma on oocyte cryopreservation before treatment in a homogeneous population of patients with Hodgkin lymphoma. The multivariate nature of this analysis minimizes confounding bias. A limitation remains the limited population size, especially in the Hasenclever subgroup analysis; one must therefore be cautious when analysing the results of this group. The patients of this cohort are still being followed in a long-term data study ['Fertilymph' (NCT05616325)] to assess the long-term impact of chemotherapy on ovarian function, fertility and psychological well-being in adolescents and young adults with lymphoma.

## CONCLUSION

Tumour aggressiveness was not found to have a significant influence on the number

of MII oocytes retrieved. These results suggest that fertility preservation should be proposed systematically in young patients with Hodgkin lymphoma, regardless of the stage, especially as the time between diagnosis and oocyte retrieval is short and no severe complications were observed. In patients with more advanced disease, inflammation may have an adverse effect on follicular growth under COH and oocyte retrieval.

## DATA AVAILABILITY

Data will be made available on request.

## ACKNOWLEDGEMENTS

The authors wish to thank Mr Andrew Thomson for his help with the English translation.

## SUPPLEMENTARY MATERIALS

Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.rbmo.2024.104448.

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Received 25 April 2024; received in revised form 26
August 2024; accepted 5 September 2024.