A 2024 meta-analysis combined the results of 38 studies investigating treatments for diminished ovarian reserve patients. DHEA, testosterone, high-dose gonadotropins and delayed start protocols all improved the number of eggs retrieved.
Patients with diminished ovarian reserve (DOR) have low AMH or AFC levels and typically have a poor ovarian response during stimulation (ie. they don’t produce many eggs). This can be seen more often with advancing female age, although younger women can also have DOR.
This post is a summary of a meta-analysis by Conforti et al. (2024) that combined the results of different studies involving therapies for patients with DOR (defined by the POSEIDON criteria with AFC <5 or AMH <1.2 ng/ml).
This paper searched for RCTs that involved treatments for DOR. The treatments included: DHEA, testosterone, high-dose gonadotropins, delayed-start protocols, letrozole, clomid, growth hormone, luteal phase stimulation, dual triggering, dual stimulation, LH, estradiol pretreatment and corifollitropin alfa.
From nearly 13,000 articles, the authors selected 38 RCTs for inclusion. A lot of the studies were excluded because they weren’t RCTs, the control groups weren’t comparable or they didn’t have a control group, they didn’t use the POSEIDON criteria, and other reasons.
🔗 Original studies are referenced in this post or within the linked Remembryo posts.
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Table of Contents
DHEA pretreatment for diminished ovarian reserve
DHEA (Dehydroepiandrosterone) is a hormone supplement that is used to potentially enhance ovarian reserve and improve fertility outcomes by increasing the production of testosterone and estrogen. Six RCTs were included: Kara et al. (2014), Yeung et al. (2014), Zhang et al. (2014), Narkwichean et al. (2017), Fu et al. (2017) and Wang et al. (2022).
In these studies, women with DOR were treated with DHEA, typically 25 mg three times daily or 75 mg daily, for periods up to 12 weeks before undergoing IVF.
When combining the results, they found that DHEA pretreatment resulted in:
- An increase in the number of eggs retrieved (average increase of 0.60, 95% CI: 0.07-1.13; p= 0.03).
- No difference in the number of mature eggs, clinical pregnancy rate, live birth rate or miscarriage rate.
Testosterone pretreatment for diminished ovarian reserve
Testosterone, an androgen needed for folliculogenesis and estradiol production, has been explored as a supplement to improve ovarian response in women with DOR. Five RCTs investigated this approach: Kim et al. (2011), Bosdou et al. (2016), Saharkhiz et al. (2018), Subirá et al. (2021) and Hoang et al. (2021).
In these studies, women with DOR were typically treated with transdermal testosterone gel, in doses ranging from 10 mg to 25 mg daily for periods from 10 days to 56 days before initiating ovarian stimulation.
When combining the results, they found that testosterone pretreatment resulted in:
- An increase in the number of eggs retrieved (average increase of 0.88, 95% CI: 0.03–1.72; p< 0.04).
- An increase in clinical pregnancy rates 2.19 times (odds ratio 2.19, 95% CI: 1.11–4.32; p = 0.01).
- An increase in live birth rates 2.19 times (OR 2.19, 95% CI: 1.11–4.32; p = 0.02).
- No difference in the number of mature oocytes or miscarriage rates.
High-dose gonadotropin for diminished ovarian reserve
Treating DOR patients with higher amounts of gonadotropins might result in more eggs, however it’s not clear how effective this strategy is. Three RCTs assessed this approach: Klinkert et al. (2005), Youssef et al. (2017) and van Tilborg et al. (2017).
These studies compared the effects of low-dose versus high-dose gonadotropins in women with DOR. Treatment typically involved 150 IU/day of FSH or up to 450 IU/day of FSH or hMG.
When combining the results, they found that low-dose gonadotropins resulted in:
- A lower number of eggs retrieved (average decrease of 1.57 eggs, 95% CI: -2.12 to -1.17; p< 0.0001).
- No difference in live birth, clinical pregnancy or miscarriage rates.
Delayed-start protocol for diminished ovarian reserve
In women with DOR, differences in how the follicles respond to treatment can be an issue during ovarian stimulation. A delayed-start protocol involves starting an initial GnRH antagonist treatment to synchronize follicular development 7 days before ovarian stimulation. This strategy has been explored in 3 RCTs: Ashrafi et al. (2018), Davar et al. (2018), and Esfidani et al. (2021).
When combining the results, they found that the delayed-start protocol resulted in:
- An increase in the number of eggs retrieved (average increase of 1.32 eggs, 95% CI: 0.74 to 1.89; p< 0.00001).
- An increase in the number of mature oocytes (average increase of 1.17 mature eggs, 95% CI: 0.42 to 1.92; p= 0.002).
- No differences in clinical pregnancy, live birth or miscarriage rates.
Letrozole for diminished ovarian reserve
Letrozole, is used to inhibit the conversion of androgens into estrogen and has been used during ovarian stimulation for women with DOR. Four RCTs focusing on its effect in DOR treatments include: Moini et al. (2019), Bastu et al. (2016), Yu et al. (2018) and Liu et al. (2020).
In these studies, letrozole was typically administered at 5 mg daily for the first 5 days of ovarian stimulation, often alongside reduced doses of gonadotropins compared to control groups.
When combining the results, they found that letrozole resulted in:
- No differences in number of eggs retrieved, number of mature eggs retrieved, clinical pregnancy rates, miscarriage rates or live birth rates.
Clomid for diminished ovarian reserve
Clomid (clomiphene citrate) functions as a selective estrogen receptor modulator, which leads to increased production of FSH and LH. This promotes the growth and maturation of ovarian follicles, leading to ovulation and making it effective for women with PCOS, who often experience irregular ovulation due to hormonal imbalances. Three RCTs explored the use of clomid for women with DOR: Ragni et al. (2012), Revelli et al. (2014) and Moffat et al. (2021).
In these trials, clomid was administered in dosages ranging from 100 mg to 150 mg for 5 to 7 days early in the cycle.
When combining the results, they found that clomid resulted in:
- No differences in number of eggs retrieved, number of mature eggs retrieved, clinical pregnancy rates, miscarriage rates or live birth rates.
Other potential treatments for diminished ovarian reserve
The rest of the treatments presented in the meta-analysis didn’t have more than 2 RCTs included, so they couldn’t combine the results. Here I’ll just summarize the main outcomes of the RCTs that were included.
Growth hormone. GH may be used in poor responders to potentially improve egg quantity and quality by promoting insulin-like growth factor 1 (IGF-1) production, which aids in egg maturation.
- Choe et al. (2018) found a higher number of mature eggs in DOR patients who were treated with 20 mg of GH three times before and during ovarian stimulation, but no change in clinical or ongoing pregnancy rates. Lee et al. (2019) found a higher number of eggs and clinical and ongoing pregnancy rates in DOR patients who were treated with 4, 4 and 2 IU of GH for 3 days during ovarian stimulation.
Luteal-Phase Stimulation. Here, the ovaries are stimulated during the luteal phase of the menstrual cycle to retrieve oocytes instead of during the follicular phase.
- Llácer et al. (2020) investigated luteal versus conventional follicular-phase stimulation, finding similar numbers of eggs retrieved, mature eggs and live births across both groups.
Dual Triggering. This strategy employs both hCG and a GnRH agonist to induce final egg maturation, aiming to improve oocyte quality and maturation.
- Keskin et al. (2023) found no difference in egg count and mature eggs between dual triggering and traditional hCG triggering, and found lower live birth rates with dual triggering.
Dual Stimulation. This involves two consecutive rounds of ovarian stimulation within a single menstrual cycle to potentially increase the yield of retrievable eggs.
- Massin et al. (2023) and Cerrillo et al. (2023) compared dual stimulation to conventional follicular stimulation in women with DOR. Cerrillo found a higher number of eggs retrieved in the control group and no change in live birth rates, while Massin reported no differences in any outcomes.
Luteinizing Hormone (LH). LH can be added to ovarian stimulation cycles, particularly for women with low-response or who are older.
- Humaidan et al. (2017) and Tosun et al. (2022) examined LH supplementation, in addition to FSH, during ovarian stimulation. Humaidan found no differences, whereas Tosun found a higher number of eggs retrieved in the control group and similar pregnancy rates compared to controls.
Estradiol Pretreatment. This involves pretreatment with estradiol to improve follicle synchronization during ovarian stimulation.
- Zhang et al. (2022) found no differences in the number of eggs retrieved or clinical pregnancy rates. Patients received 2 mg of estradiol twice daily on day 7 after ovulation until day 2 of the next cycle.
Corifollitropin Alfa. This is a long-acting gonadotropin used in ovarian stimulation instead of FSH.
- Drakopoulos et al. (2017) found no differences. Fusi et al. (2020) found higher numbers of retrieved eggs, mature eggs and ongoing pregnancies with corifollitropin alpha supplementation.
Conclusion
Women with DOR who supplemented with DHEA before ovarian stimulation showed an increase in the number of eggs retrieved. Higher gonadotropin doses also resulted in more eggs.
Pretreatment with testosterone gel increased the number of eggs and improved pregnancy outcomes like live birth rates.
Delayed start protocols, involving an initial GnRH antagonist treatment before ovarian stimulation, increased the number of eggs and the number of mature eggs.
Letrozole and clomid didn’t show any improvements for DOR patients, at least based on the RCTs included.
Additional strategies like growth hormone, luteal-phase stimulation, dual triggering, dual stimulation, the use of LH, estradiol pretreatment and the use of corifollitropin alfa were also explored, with mixed results. There were fewer RCTs addressing these treatments in the meta-analysis.
Reference
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About Embryoman
Embryoman (Sean Lauber) is a former embryologist and the founder of Remembryo, an IVF research and fertility education website. After working in an IVF lab in the US, he returned to Canada and now focuses on making fertility research more accessible. He holds a Master’s in Immunology and launched Remembryo in 2018 to help patients and professionals make sense of IVF research. Sean shares weekly study updates on Facebook, Instagram, and Reddit regularly. He also answers questions on Reddit or in his private Facebook group.
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