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M Grynberg, S Pytel, M Peigne, C Sonigo, The follicular output rate in normo-ovulating women undergoing ovarian stimulation is increased after unilateral oophorectomy, Human Reproduction, Volume 38, Issue 6, June 2023, Pages 1162–1167, https://doi.org/10.1093/humrep/dead056
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Abstract
Does unilateral oophorectomy modify the antral follicular responsiveness to exogenous FSH, assessed by the Follicular Output RaTe (FORT) in normo-ovulating women?
Antral follicle responsiveness to exogenous FSH, as assessed by the FORT index, is significantly higher in women with a single ovary in comparison with the ipsilateral ovary of age-matched controls.
Growing evidence indicates that the innovative FORT may be a remarkable tool to evaluate the follicle responsiveness to exogenous FSH, independently of the size of the pretreatment cohort of small antral follicles. It is conceivable that in the unclear compensating mechanisms at play in women having undergone unilateral oophorectomy, an increase in the sensitivity of antral follicles to FSH may be involved. To clarify this issue, we decided to investigate whether the responsiveness of follicles to exogenous FSH, as assessed by the FORT, is altered in unilaterally oophorectomized patients.
The study included 344 non-polycystic ovary syndrome, non-endometriotic women, aged 22–43 years old. There were 86 women who had a single ovary as a result of unilateral oophorectomy or adnexectomy (Single Ovary group; average time since surgery: 52 (8–156) months), and each of them was retrospectively matched with three patients having two intact ovaries, according to age (±1 year), year of ovarian stimulation, and FSH starting dose (±50 IU) (Control group, n = 258).
Serum anti-Mullerian hormone (AMH) levels and total antral follicle count (AFC) (3–12 mm) were assessed on cycle day 3 in both groups. In all patients, follicles were counted before exogenous FSH administration (baseline) and on the day of oocyte trigger (OT) (dOT; preovulatory follicles; 16–22 mm). Antral follicle responsiveness to FSH was estimated in both groups by the FORT, determined by the ratio of the preovulatory follicle count on dOT × 100 to the small AFC at baseline. FORT in the Single Ovary group was compared to the overall FORT considering both ovaries or the index calculated on the ipsilateral ovary of matched controls.
Overall, serum AMH levels and total AFC (1.0 (0.5–2.1) vs 1.8 (1.0–3.3), P < 0.005) and (9.0 (6.0–17.0) vs 13.0 (8.0–21.0), P < 0.001, respectively) were lower in the Single Ovary group compared to the Control group. When considering the FORT calculated on the basis of the overall ovarian response in women with two ovaries, the results were similar when compared to those obtained in patients unilaterally oophorectomized (30.4% (15.6–50.0) vs 32.5% (14.0–50.0), respectively). Interestingly, the comparison of FORT between women with a single ovary and the ipsilateral ovary of age-matched controls, revealed, after adjustment for AMH and AFC, a significantly higher ratio after unilateral oophorectomy (32.5% (14.8–50.0) vs 25.0% (10.0–50.0), P < 0.002, respectively).
This study was based on retrospective data in a limited population. In addition, the FORT index has inherent limitations due to its indirect assessment of follicular responsiveness to FSH.
The present investigation provides evidence that the responsiveness of antral follicles to exogenous FSH is increased in women having undergone unilateral oophorectomy when compared to the ipsilateral ovary of age-matched controls. This is consistent with the implication of a compensating phenomenon that drives the follicular changes in unilaterally oophorectomized patients. Further studies directly assessing the granulosa cell function and the density of FSH receptors in small antral follicles are required to confirm our findings.
The authors have no funding or competing interests to declare.
N/A.
Introduction
Several lines of evidence indicate that the number of mature oocytes recovered following ovarian stimulation represents a major issue for IVF success rates. However, the mechanisms that drive the capacity of the ovaries to respond to exogenous gonodotropin administration are highly complex and not fully established. Although the overall number of small antral follicles constitutes a key point, the inherent sensitivity of each individual antral follicle to FSH is also at play. The Follicular Output RaTe (FORT) index, represented by the ratio between the number of follicles that reach preovulatory maturation in response to FSH and the available pool of FSH-sensitive follicles, has been reported as a unique tool for assessing the follicle responsiveness to exogenous FSH. This measure which is independent of the size of pretreatment cohort of small antral follicles, contrary to the absolute number of mature follicles and oocytes obtained at the end of ovarian stimulation (Genro et al., 2011), may be considered as possible qualitative marker of the ovarian function, since it is related to IVF outcome in normo-cycling women devoid of polycystic ovaries (Gallot et al., 2012).
Women having a single ovary as a result of unilateral oophorectomy or adnexectomy represent a specific model of ovarian aging, since they abruptly lose half of their primordial follicular stockpile. Previous studies have suggested that major alterations in folliculogenesis can sometimes occur to preserve and maintain ovarian function. Indeed, the decline of anti-Mullerian hormone (AMH) levels was reported to occur more gradually in patients with low age-specific baseline levels of AMH compared to that in patients with high age-specific AMH levels (de Kat et al., 2016). Furthermore, the onset of menopause remains unchanged or relatively early in women who have undergone unilateral oophorectomy (Faddy et al., 1992; Faddy and Gosden, 1995; McGee and Hsueh, 2000; Yasui et al., 2012; Bjelland et al., 2014), indicating the existence of mechanisms that maintain ovarian function in this situation. Thus, in the remaining ovary, the initial follicular recruitment might be slower, resulting fewer follicles initiating growth and a smaller number of growing follicle. However, we recently showed that ‘per-ovary’ and ‘per-follicle’ AMH production, as well as antral follicle distribution, in unilaterally oophorectomized women was comparable to that of matched controls, arguing against the implication of AMH in the mechanisms driving follicle loss in the remaining ovary (Grynberg et al., 2021). Regarding the capacity of women with a single ovary to respond to ovarian stimulation, several studies have reported, predictably, a lower number of oocytes recovered when compared with patient having two ovaries (Al-Hasani et al., 2003; Levi et al., 2003; Hendricks et al., 2010; Lass, 2018; Rodriguez-Wallberg et al., 2022). Apart from this absolute number of metaphase II oocytes, the antral follicle responsiveness to FSH in these women with modified folliculogenesis has been questioned, suggesting a possible reduced ovarian sensitivity to gonadotropins (Al-Hasani et al., 2003; Levi et al., 2003; Hendricks et al., 2010; Lass, 2018; Rodriguez-Wallberg et al., 2022). However, that point remains subject to debate. The present investigation aimed to clarify whether unilaterally oophorectomy modifies the antral follicle responsiveness to FSH as assessed by the FORT.
Materials and methods
Subjects
Our study included 344 women, aged 22–43 years old, with a single ovary as a result of unilateral oophorectomy/adnexectomy (Single Ovary group), who underwent ovarian stimulation for infertility treatment or non-urgent fertility preservation between 2014 and 2021. All of them met the following inclusion criteria: (i) regular menstrual cycles lasting between 25 and 35 days; (ii) correct visualization of the remaining ovary devoid of abnormality on transvaginal ultrasound scan; and (iii) ovarian stimulation using GnRH antagonist protocol after 17β‐estradiol (E2) pretreatment. Women with a history of chemotherapy or current diseases affecting either ovaries (polycystic ovary syndrome, endometriomas, ovarian cysts) or gonadotropin or sex steroid secretion, clearance or excretion were not included. Each woman was retrospectively matched with three patients having both ovaries, according to age (±1 year), year of ovarian stimulation, and FSH starting dose (±50 IU). The study was approved by the Institutional Review Board of Antoine Béclère University Hospital.
Ovarian stimulation protocol
Ovarian stimulation for IVF-ET or non-urgent fertility preservation was performed using GnRH antagonist protocols. Infertile women received micronized 17β‐E2 oral tablets (4 mg/day; Provamès®, Norgine Laboratories, France) from Day 20 of one cycle until Day 2 of their next cycle. After confirmation of the antral follicular cohort homogeneity (cycle day 3), 17β‐E2 was discontinued and rec-FSH treatment (Gonal-F®, Merck Laboratories, France or Bemfola®, Gedeon Richter Laboratories, France) was started for 5 days at a dose individualized according to ovarian reserve tests markers at baseline and on the antral follicle count (AFC) measured on cycle day 3 under 17β‐E2. Pituitary down-regulation was achieved with a daily 0.25 mg GnRH antagonist injection of either cetrorelix (Cetrotide®, Merck Pharmaceuticals) or ganirelix (Orgalutran®, Merck Sharp & Dohme) starting on Day 6 of ovarian stimulation. From Day 6 of rec-FSH therapy onwards, daily FSH doses were adjusted according to E2 levels and/or the number of growing follicles. During the last days of ovarian stimulation, patients had daily visits at our institution for ultrasonographic and hormonal examinations to define the proper timing for the ovulation trigger. Administration of hCG (250 µg of Ovitrelle, Merck Serono, Lyon, France) or GnRH agonist (triptorelin 0.1 mg, Decapeptyl®, Ipsen Pharmaceuticals, 0.2 mg, S.C.) was performed as soon as ≥1 (single ovary) or 2 (controls) preovulatory follicles (16–22 mm in diameter) were observed in and E2 levels per preovulatory follicle were >200 pg/ml. Oocytes were retrieved 36 h after the day of oocyte trigger (dOT) by transvaginal ultrasound-guided aspiration.
FORT calculation and other markers of ovarian responsiveness to FSH
On cycle day 3 under 17β‐E2 and on the dOT, ovarian ultrasound scans were performed to evaluate the number and sizes of antral follicles. We carefully determined, the number of all follicles measuring 3–9 mm in diameter (AFC) and, on dOT, the number of all follicles measuring 16–22 mm in diameter (preovulatory follicle count, PFC), in both ovaries.
The FORT was calculated by the ratio between PFC on dOT × 100/AFC on cycle day 3 under 17β‐E2. The choice of considering only 16–22 mm follicles for the calculation of FORT was used in previous investigations of our group (Genro et al., 2011; Gallot et al., 2012) and represented a methodological attempt for discriminating, among the cohort of small antral follicles, those that were the most FSH-responsive.
Our analysis aimed at comparing the antral follicle responsiveness to exogenous FSH among women with a single ovary and women with two ovaries. We used two different methodologies for analyzing the control group (i.e. having two ovaries): (i) a calculation of the FORT index from the one single ovary (the same as women with a single ovary); (ii) a calculation of the overall FORT index considering both ovaries.
In combination with the FORT, we used two other surrogate markers of ovarian sensitivity to FSH: (i) the follicle to oocyte index (FOI), calculated as the number of oocytes recovered × 100/AFC (Alviggi et al., 2018), and (ii) the ovarian sensitivity index (OSI), calculated as the number of oocytes recovered × 1000/total dose of FSH (Li et al., 2014). Since we only had data available on the overall number of oocytes recovered, without details on oocytes yielded per ovary, we could not use these two markers for the subanalysis comparing women with a single ovary and the ipsilateral ovary of matched controls.
Hormonal measurements
Serum AMH levels were determined using an ultrasensitive enzyme-linked immunosorbent assay (ELISA) (Beckman-Coulter, Villepinte, France). Intra- and interassay coefficients of variation were inferior to 6% and 10%, respectively. The minimal detection limit was 0.13 ng/ml, and linearity was up to 21 ng/ml.
Ultrasound scan
Ultrasound scans were performed by one single operator using a 3.7–9.3 MHz multi-frequency transvaginal probe (RIC5-9H, Voluson E8, General Electric Medical Systems, Paris, France). The operator was blinded to results of hormone assays. The objective of ultrasound examination was to determine the number and size of small antral follicles. All follicles with a mean diameter of 3–12 mm (mean of two orthogonal diameters) were considered. To optimize the reliability of ovarian follicular assessment, the ultrasound scanner was equipped with a tissue harmonic imaging system (Thomas and Rubin, 1998), enabling a higher image resolution quality and an optimal recognition of follicular borders. Intra-analysis coefficient variation for follicular and ovarian measurements were <5% and their minimal detection limit was 0.1 mm.
Statistics
All variables were expressed as number of cases (n), percentage of occurrence (%), and median (interquartile range (25–75%)). Our study compared women with a single ovary, matched with three patients having both ovaries. Comparisons of groups with a ratio 1:3 were performed using univariate or multivariate conditional logistic regression models, which require categorical variables. Therefore, all variables have been changed to categorical after stratification of the whole population into three classes (terciles). A P-value <0.05 was considered statistically significant. All statistics were performed using NCSS Statistical Software (2021) (‘NCSS 2021 Statistical Software (2021). NCSS. LCC. Kaysville, UT, USA. Ness.com/software/’, n.d.).
Results
Overall population characteristics
We studied 344 patients (Single Ovary group: n = 86; Control group: n = 258). The overall, age of the population was of 34.0 (29.0–36.0) years old. The women with a single ovary had undergone unilateral oophorectomy (n = 55) or adnexectomy (n = 31). The indication for oophorectomy was benign ovarian cyst (52%) or ectopic pregnancy (8%). For adnexectomy, the indication was torsion (59%), borderline tumor (27%), or ectopic pregnancy (14%). Among the 86 patients having undergone ovarian surgery, the average time between the procedure and hormono-follicular assessment was 52 (8–156) months.
Patients’ and follicle characteristics in the two groups are described in Table I. Overall, age and BMI were similar between both groups (34.0 (29.5–36.0) vs 34.0 (29.0–36.0) and 24.6 (20.2–27.3) vs 24.1 (20.9–26.8), respectively). Women having two ovaries showed higher serum AMH levels (1.8 (1.0–3.3) vs 1.0 (0.5–2.1), P < 0.005) and baseline AFC (13.0 (8.0–21.0) vs 9.0 (6.0–17.0), P < 0.001) when compared with those with a single ovary.
| . | Single Ovary (n = 86) . | Controls (n = 258) . | P . |
|---|---|---|---|
| Age (years) | 34.0 [29.5–36.0] | 34.0 [29.0–36.0] | — |
| BMI (kg/m2) | 24.6 [20.2–27.3] | 24.1[20.9–26.8] | — |
| Serum AMH levels (ng/ml) | 1.0 [0.5–2.1] | 1.8 [1.0–3.3] | <0.005 |
| No. of antral follicles 3–9 mm | 9.0 [6.0–17.0] | 13.0 [8.0–21.0] | <0.001 |
| Single ovary etiology, n (%) | |||
| Adnexectomy | 31 (36.0%) | — | |
| Oophorectomy | 55 (64.0%) | ||
| Indication for ovarian stimulation, n (%) | |||
| Infertility | 44 (51.2%) | ||
| Fertility preservation | 42 (48.8%) | — |
| . | Single Ovary (n = 86) . | Controls (n = 258) . | P . |
|---|---|---|---|
| Age (years) | 34.0 [29.5–36.0] | 34.0 [29.0–36.0] | — |
| BMI (kg/m2) | 24.6 [20.2–27.3] | 24.1[20.9–26.8] | — |
| Serum AMH levels (ng/ml) | 1.0 [0.5–2.1] | 1.8 [1.0–3.3] | <0.005 |
| No. of antral follicles 3–9 mm | 9.0 [6.0–17.0] | 13.0 [8.0–21.0] | <0.001 |
| Single ovary etiology, n (%) | |||
| Adnexectomy | 31 (36.0%) | — | |
| Oophorectomy | 55 (64.0%) | ||
| Indication for ovarian stimulation, n (%) | |||
| Infertility | 44 (51.2%) | ||
| Fertility preservation | 42 (48.8%) | — |
Patients were matched on age (±1 year), starting FSH dose (±50 IU), and year of ovarian stimulation with three controls for one single ovary patient.
Results are expressed in median [25–75%], P-value of conditional logistic regression.
AMH: anti-Mullerian hormone.
| . | Single Ovary (n = 86) . | Controls (n = 258) . | P . |
|---|---|---|---|
| Age (years) | 34.0 [29.5–36.0] | 34.0 [29.0–36.0] | — |
| BMI (kg/m2) | 24.6 [20.2–27.3] | 24.1[20.9–26.8] | — |
| Serum AMH levels (ng/ml) | 1.0 [0.5–2.1] | 1.8 [1.0–3.3] | <0.005 |
| No. of antral follicles 3–9 mm | 9.0 [6.0–17.0] | 13.0 [8.0–21.0] | <0.001 |
| Single ovary etiology, n (%) | |||
| Adnexectomy | 31 (36.0%) | — | |
| Oophorectomy | 55 (64.0%) | ||
| Indication for ovarian stimulation, n (%) | |||
| Infertility | 44 (51.2%) | ||
| Fertility preservation | 42 (48.8%) | — |
| . | Single Ovary (n = 86) . | Controls (n = 258) . | P . |
|---|---|---|---|
| Age (years) | 34.0 [29.5–36.0] | 34.0 [29.0–36.0] | — |
| BMI (kg/m2) | 24.6 [20.2–27.3] | 24.1[20.9–26.8] | — |
| Serum AMH levels (ng/ml) | 1.0 [0.5–2.1] | 1.8 [1.0–3.3] | <0.005 |
| No. of antral follicles 3–9 mm | 9.0 [6.0–17.0] | 13.0 [8.0–21.0] | <0.001 |
| Single ovary etiology, n (%) | |||
| Adnexectomy | 31 (36.0%) | — | |
| Oophorectomy | 55 (64.0%) | ||
| Indication for ovarian stimulation, n (%) | |||
| Infertility | 44 (51.2%) | ||
| Fertility preservation | 42 (48.8%) | — |
Patients were matched on age (±1 year), starting FSH dose (±50 IU), and year of ovarian stimulation with three controls for one single ovary patient.
Results are expressed in median [25–75%], P-value of conditional logistic regression.
AMH: anti-Mullerian hormone.
Ovarian stimulation characteristics and FORT analysis
The outcomes of the ovarian stimulation cycles are presented in Tables II and III. After similar FSH starting doses (by design) and durations of ovarian stimulation, the PFC on the dOT was significantly lower in the Single Ovary group when compared to controls (3 (1–5) vs 4 (2–6), P < 0.01). As expected, the number of retrieved and matured oocytes was also significantly higher in the Control group. However, analysis of FORT between women with one or two ovaries did not show a significant difference (32.5% (14.0–50.0) vs 30.4% (15.6–50.0), respectively). In, addition, two other surrogate markers of ovarian sensitivity to FSH failed to find any difference between both groups (FOI: 75 (42.5–110.8) vs 65 (43.7–100.0) and OSI: 2.2 (1.2–4.9) vs 3.1 (1.6–5.9), respectively). After multivariate analysis and adjustment on AMH and baseline AFC, none of the ovarian stimulation outcomes (PFC on dOT, number of oocytes retrieved, and number of mature oocytes) were statistically different.
| . | Single Ovary (n = 86) . | Controls (n = 258) . | P . | P* . |
|---|---|---|---|---|
| Total dose of FSH (IU) | 3000 [2156–4125] | 3000 [2100–4050] | 0.39 | |
| Duration (days) | 11 [9–12] | 11 [10–12] | 0.99 | |
| No. of preovulatory follicles 16–22 mm | 3 [1–5] | 4 [2–6] | 0.01 | 0.48 |
| FORT index (%) | 32.5 [14.0–50.0] | 30.4 [15.6–50.0] | 0.95 | 0.84 |
| No. of retrieved oocytes | 7.0 [5.0–11.8] | 9.0 [6.0–14.0] | 0.005 | 0.61 |
| No. of mature oocytes | 6.0 [3.0–9.0] | 7.0 [5.0–12.0] | 0.04 | 0.91 |
| FOI (%) | 75 [42.5–110.8] | 65 [43.7–100.0] | 0.95 | 0.98 |
| OSI | 2.2 [1.2–4.9] | 3.1 [1.6–5.9] | 0.40 | 0.96 |
| . | Single Ovary (n = 86) . | Controls (n = 258) . | P . | P* . |
|---|---|---|---|---|
| Total dose of FSH (IU) | 3000 [2156–4125] | 3000 [2100–4050] | 0.39 | |
| Duration (days) | 11 [9–12] | 11 [10–12] | 0.99 | |
| No. of preovulatory follicles 16–22 mm | 3 [1–5] | 4 [2–6] | 0.01 | 0.48 |
| FORT index (%) | 32.5 [14.0–50.0] | 30.4 [15.6–50.0] | 0.95 | 0.84 |
| No. of retrieved oocytes | 7.0 [5.0–11.8] | 9.0 [6.0–14.0] | 0.005 | 0.61 |
| No. of mature oocytes | 6.0 [3.0–9.0] | 7.0 [5.0–12.0] | 0.04 | 0.91 |
| FOI (%) | 75 [42.5–110.8] | 65 [43.7–100.0] | 0.95 | 0.98 |
| OSI | 2.2 [1.2–4.9] | 3.1 [1.6–5.9] | 0.40 | 0.96 |
Multivariate analysis, after adjustment for AMH (anti-Mullerian hormone) and AFC (antral follicle count).
Results are expressed in median [25–75%], P-value of univariate conditional logistic regression.
FORT (follicular output rate) = number of follicules ≥16–20 mm on day of hCG × 100/AFC at the beginning of ovarian stimulation.
FOI (follicle to oocyte index) = number of oocytes recovered × 100/AFC.
OSI (ovarian sensitivity index) = number of oocytes recovered × 1000/total dose of FSH.
| . | Single Ovary (n = 86) . | Controls (n = 258) . | P . | P* . |
|---|---|---|---|---|
| Total dose of FSH (IU) | 3000 [2156–4125] | 3000 [2100–4050] | 0.39 | |
| Duration (days) | 11 [9–12] | 11 [10–12] | 0.99 | |
| No. of preovulatory follicles 16–22 mm | 3 [1–5] | 4 [2–6] | 0.01 | 0.48 |
| FORT index (%) | 32.5 [14.0–50.0] | 30.4 [15.6–50.0] | 0.95 | 0.84 |
| No. of retrieved oocytes | 7.0 [5.0–11.8] | 9.0 [6.0–14.0] | 0.005 | 0.61 |
| No. of mature oocytes | 6.0 [3.0–9.0] | 7.0 [5.0–12.0] | 0.04 | 0.91 |
| FOI (%) | 75 [42.5–110.8] | 65 [43.7–100.0] | 0.95 | 0.98 |
| OSI | 2.2 [1.2–4.9] | 3.1 [1.6–5.9] | 0.40 | 0.96 |
| . | Single Ovary (n = 86) . | Controls (n = 258) . | P . | P* . |
|---|---|---|---|---|
| Total dose of FSH (IU) | 3000 [2156–4125] | 3000 [2100–4050] | 0.39 | |
| Duration (days) | 11 [9–12] | 11 [10–12] | 0.99 | |
| No. of preovulatory follicles 16–22 mm | 3 [1–5] | 4 [2–6] | 0.01 | 0.48 |
| FORT index (%) | 32.5 [14.0–50.0] | 30.4 [15.6–50.0] | 0.95 | 0.84 |
| No. of retrieved oocytes | 7.0 [5.0–11.8] | 9.0 [6.0–14.0] | 0.005 | 0.61 |
| No. of mature oocytes | 6.0 [3.0–9.0] | 7.0 [5.0–12.0] | 0.04 | 0.91 |
| FOI (%) | 75 [42.5–110.8] | 65 [43.7–100.0] | 0.95 | 0.98 |
| OSI | 2.2 [1.2–4.9] | 3.1 [1.6–5.9] | 0.40 | 0.96 |
Multivariate analysis, after adjustment for AMH (anti-Mullerian hormone) and AFC (antral follicle count).
Results are expressed in median [25–75%], P-value of univariate conditional logistic regression.
FORT (follicular output rate) = number of follicules ≥16–20 mm on day of hCG × 100/AFC at the beginning of ovarian stimulation.
FOI (follicle to oocyte index) = number of oocytes recovered × 100/AFC.
OSI (ovarian sensitivity index) = number of oocytes recovered × 1000/total dose of FSH.
| . | Single Ovary (n = 86) . | Controls (n = 258) . | P . | P* . |
|---|---|---|---|---|
| No. of follicles 3–9 mm | 9.0 [6.0–17.0] | 7.0 [4.0–11.0] | <0.001 | |
| No. of preovulatory follicles 16–22 mm | 3.0 [1.0–5.0] | 2.0 [1.0–3.0] | <0.001 | 0.001 |
| FORT index (%) | 32.5 [14.0–50.0] | 25.0 [10.0–50.0] | 0.21 | 0.002 |
| . | Single Ovary (n = 86) . | Controls (n = 258) . | P . | P* . |
|---|---|---|---|---|
| No. of follicles 3–9 mm | 9.0 [6.0–17.0] | 7.0 [4.0–11.0] | <0.001 | |
| No. of preovulatory follicles 16–22 mm | 3.0 [1.0–5.0] | 2.0 [1.0–3.0] | <0.001 | 0.001 |
| FORT index (%) | 32.5 [14.0–50.0] | 25.0 [10.0–50.0] | 0.21 | 0.002 |
Multivariate analysis, after adjustment for AMH (anti-Mullerian hormone) and AFC (antral follicle count).
Results are expressed in median [25–75%], P-value of univariate conditional logistic regression.
FORT (follicular output rate) = number of follicules ≥16–20 mm on day of hCG × 100/AFC at the beginning of ovarian stimulation.
| . | Single Ovary (n = 86) . | Controls (n = 258) . | P . | P* . |
|---|---|---|---|---|
| No. of follicles 3–9 mm | 9.0 [6.0–17.0] | 7.0 [4.0–11.0] | <0.001 | |
| No. of preovulatory follicles 16–22 mm | 3.0 [1.0–5.0] | 2.0 [1.0–3.0] | <0.001 | 0.001 |
| FORT index (%) | 32.5 [14.0–50.0] | 25.0 [10.0–50.0] | 0.21 | 0.002 |
| . | Single Ovary (n = 86) . | Controls (n = 258) . | P . | P* . |
|---|---|---|---|---|
| No. of follicles 3–9 mm | 9.0 [6.0–17.0] | 7.0 [4.0–11.0] | <0.001 | |
| No. of preovulatory follicles 16–22 mm | 3.0 [1.0–5.0] | 2.0 [1.0–3.0] | <0.001 | 0.001 |
| FORT index (%) | 32.5 [14.0–50.0] | 25.0 [10.0–50.0] | 0.21 | 0.002 |
Multivariate analysis, after adjustment for AMH (anti-Mullerian hormone) and AFC (antral follicle count).
Results are expressed in median [25–75%], P-value of univariate conditional logistic regression.
FORT (follicular output rate) = number of follicules ≥16–20 mm on day of hCG × 100/AFC at the beginning of ovarian stimulation.
Subsequent analyses were performed considering only one ovary in the Control group (Table III). The AFC at baseline and the number of preovulatory follicles on the dOT were significantly higher in Single Ovary group when compared to the ipsilateral ovary in Controls (9.0 (6.0–17.0) vs 7.0 (4.0–11.0) follicles, P < 0.001 and 3.0 (1.0–5.0) vs 2.0 (1.0–3.0) follicles, respectively). The comparison of FORT between women with a single ovary and the ipsilateral ovary of age-matched controls was not significantly different (32.5% (14.0–50.0) vs 25.0% (10.0–50.0), P = 0.21). Nevertheless, after adjustment for serum AMH levels and baseline AFC on one ovary, the analyses revealed both a higher PFC on the dOT and a higher FORT ratio after unilateral oophorectomy (P < 0.001 and P = 0.002, respectively).
Discussion
The present study was designed to investigate the effect of unilateral oophorectomy on the capacity of small antral follicles to respond to exogenous FSH administration. Several lines of evidence indicate that women having a single ovary as a result of unilateral oophorectomy do not show an early menopause onset (Danforth et al., 1989). Although the precise mechanisms at play remain unknown, a slower initial follicular recruitment in the remaining ovary might be involved and would lead to a lower number of follicles initiating growth and to a smaller number of growing follicles. We recently tried to clarify this issue by performing an extensive hormonal and follicular evaluation to compare patients with a single remaining ovary after unilateral oophorectomy to controls who have both ovaries intact. We found that unilateral oophorectomy did not modify the strength of the correlation between serum AMH levels and AFC (Grynberg et al., 2021). In addition, the remarkable steadiness of the per-ovary and per-follicle production of AMH in unilaterally oophorectomized is inconsistent with the implication of AMH in the mechanisms affecting follicle loss in the remaining ovary (Grynberg et al., 2021).
Apart from the quantitative changes in the folliculogenesis process, we wanted to assess whether the responsiveness of small antral follicles to FSH was modified. Indeed, some studies have suggested a possible reduced ovarian sensitivity of antral follicles to exogenous gonadotropins after unilateral oophorectomy (Al-Hasani et al., 2003; Levi et al., 2003; Hendricks et al., 2010; Lass, 2018; Rodriguez-Wallberg et al., 2022) on the basis of a lower number of oocytes recovered after ovarian stimulation despite the use of higher doses of gonadotropins administered (Al-Hasani et al., 2003; Levi et al., 2003; Hendricks et al., 2010; Lass, 2018; Rodriguez-Wallberg et al., 2022). However, the ovarian response of antral follicles to exogenous FSH is a function not only of the pretreatment size of the antral follicle pool but also their inherent sensitivity to FSH. Although unilaterally oophorectomized women predictably show lower ovarian reserve markers when compared to age-matched controls (Grynberg et al., 2021), the responsiveness of their antral follicle to stimulation has never been analyzed. So far, direct assessment of ovarian sensitivity to FSH is impossible. Over the past decade, several indexes have been developed to indirectly estimate this important parameter of ovarian stimulation efficiency. Thus, previous investigations have demonstrated that the FORT index is a tool to indirectly assess the antral follicle responsiveness to exogenous FSH (Genro et al., 2011; Gallot et al., 2012; Zhang et al., 2013). So far, FORT has been negatively correlated to serum AMH levels in normo-ovulating women and has been discussed as a qualitative marker of the ovarian function (Genro et al., 2011). The present study shows that women who were unilaterally oophorectomized had comparable FORTs as controls. Similarly, FOI and OSI, two other surrogate markers of ovarian sensitivity to FSH, were comparable between the two groups. However, when compared to the ipsilateral ovary of age-matched controls, we observed, after adjustment for serum AMH levels and baseline AFC, a significantly higher follicular sensitivity of antral follicle to FSH. This might be an adaptative mechanism to optimize follicular and ovarian function in women with a single remaining ovary, since FORT has been previously reported to be positively related to IVF outcomes (Gallot et al., 2012; Zhang et al., 2013). Indeed, although women with only one ovary produce an overall reduced number of oocytes when compared with those having two ovaries, their IVF outcomes remain similar (Khan et al., 2014; Lass, 2018), suggesting intact gametic competence. However, the analysis of the fate of oocytes originating from women with a single ovary was not possible since many of them where included in a non-urgent fertility preservation program and had not yet used their frozen oocytes. The precise mechanisms involved in the possible increased responsiveness to FSH might be a higher density of FSH receptors on the granulosa cells of small antral follicles within the remaining ovary after unilateral oophorectomy.
Previous studies have suggested that major folliculogenesis rearrangements occur to preserve and maintain ovarian function despite the abrupt depletion of the ovarian reserve following unilateral oophorectomy (Faddy et al., 1992; Faddy and Gosden, 1995; McGee and Hsueh, 2000; Yasui et al., 2012; Bjelland et al., 2014). Although the mechanisms at play remain poorly understood, a possible role for AMH has recently been judged as inconsistent (Grynberg et al., 2021). However, the higher AFC we observed in women who were unilaterally oophorectomized compared to the ipsilateral ovary in controls might be considered as an adaptative mechanism of the folliculogenesis process after the removal of one ovary.
The significance of the present results should take into account both the retrospective nature of study and some limitations of the FORT index, as discussed elsewhere (Genro et al., 2011; Gallot et al., 2012). First, this ratio is based on ultrasound evaluation, which is a subjective operator-dependant variation. Secondly, FORT supposes that only small antral follicles (3–8 mm at d0) respond to FSH, but it is possible that differences exist in the FSH-driven growth according to follicle size (Fanchin et al., 2005). Moreover, FORT measurements assume that on the dOT, only follicles that have reached 16–22 mm have effectively respond to FSH. Nevertheless, it is conceivable that smaller follicles have also presented some degree of FSH responsiveness (Fanchin et al., 2005). In addition, FSH receptor polymorphisms (Perez Mayorga et al., 2000), which are supposed to be involved in follicle responsiveness to FSH, have not been analyzed in the studied population.
In conclusion, the present investigation provides evidence that the responsiveness of antral follicles to exogenous FSH is increased in women who have undergone unilateral oophorectomy when compared to that in the ipsilateral ovary of age-matched controls. This is consistent with an implication of a compensating phenomenon that drives the follicular changes in unilaterally oophorectomized patients.
Data availability
The data underlying this article will be shared upon reasonable request to the corresponding author.
Authors’ roles
Wrote the paper: M.G. Proofread English text: M.G. Conceived and designed the study: M.G. and C.S. Analyzed the data: C.S. and M.G. Contributed to materials/analysis tools: S.P., M.P., C.S., and M.G.
Funding
The authors have no funding sources to declare.
Conflict of interest
The authors have no conflict of interest to declare.
