Personalized In Vitro Fertilization Protocols in Premature Ovarian Insufficiency and Male-Factor Infertility: A Case Series

Introduction

Primary infertility, particularly among women with premature ovarian insufficiency (POI), is a growing challenge in reproductive medicine, often requiring intricate and personalized treatment approaches to achieve successful outcomes [1]. POI is typically characterized by low levels of anti-Müllerian hormone (AMH), an indicator of a woman’s remaining ovarian follicle count and overall fertility potential [2]. Lower AMH levels correspond with reduced response to ovarian stimulation, leading to fewer available oocytes and, consequently, lower pregnancy rates [3]. This challenge is further compounded when male-factor infertility, such as oligoasthenoteratozoospermia (OAT) – a condition marked by low sperm count, poor motility, and abnormal morphology – is also present [4]. Both POI and OAT have shown substantial challenges in assisted reproductive technology, limiting options and complicating treatment protocols to achieve successful conception [5,6]. For patients dealing with both POI and male infertility, standard reproductive treatments may be less effective. Personalized approaches, including targeted ovarian stimulation, sperm improvement methods, and careful embryo transfer planning, might be needed [7,8]. Emerging research highlights the potential benefits of adjuvant therapies, such as growth hormone and modifications in FSH and LH dosages, aimed at enhancing ovarian response and embryo quality in women with low ovarian reserve. However, there remains no universally effective approach, and treatment must be continually adapted to patient response. This report examines 4 cases of primary infertility involving POI and male-factor infertility, with an emphasis on individualized treatment approaches, including ovarian stimulation adjustments, embryo transfer choices, and outcome variability. This report aims to bridge that gap by detailing the clinical decision-making and outcomes of 4 cases, offering insights into optimizing treatment for similar patients. Additionally, these 4 cases were selected based on their extreme AMH levels, varied male-factor infertility presentations, and distinct treatment adaptations, allowing for a comprehensive evaluation of protocol effectiveness. In clinical practice, patients with low AMH often present with varying degrees of male-factor infertility. This case series explores how individualized protocols can be tailored to the patient’s ovarian reserve and male-factor infertility, reflecting the complexity of real-world scenarios. While varying male factors (from normozoospermia to OAT) introduce additional challenges, the outcomes still provide insight into managing POI and male infertility.

Case Reports

CASE 1:

A 30-year-old woman presented with an 8-year history of infertility. Her primary concern was difficulty conceiving. She had irregular menstrual cycles and no significant gynecological history. She had previously undergone 1 unsuccessful in vitro fertilization (IVF) attempt. Her AMH serum level was measured at 0.247 ng/mL. The male partner, aged 39 years, had OAT, with a sperm concentration of 2.005 million/mL, progressive motility of 12%, and 1% normal morphology. He was treated with coenzyme Q10 and multivitamins, and sperm washing was performed to improve motility. The male partner’s semen analysis revealed OAT, with a sperm concentration of 2.005 million/mL, progressive motility of 12%, and morphology of only 1% normal forms, further complicating their infertility. The patient underwent controlled ovarian hyperstimulation using an agonist protocol with Follitropin delta at a dose of 20 U (FSH 300 IU) and LH 75 IU. On Days 6–12 of stimulation, growth hormone (GH) 9 mg on D6 was administered as an adjuvant to support follicular development. GH was initiated on Day 6 due to suboptimal follicular growth observed during early monitoring, aiming to enhance follicular response without overstimulation. Despite the challenges of both diminished ovarian reserve and male-factor infertility, oocyte retrieval was performed, and 2 Day-5 blastocysts were transferred in a fresh cycle. Luteal phase support was provided with micronized progesterone at a dose of 800 mg daily. Unfortunately, the cycle did not result in pregnancy, as confirmed by a negative β-hCG test. No adverse events were reported during the treatment process.

CASE 2:

A 29-year-old woman presented with a history of 2 years of marriage and primary infertility. Laboratory testing revealed an AMH level of 0.08 ng/mL, indicating severely diminished ovarian reserve. After evaluating the patient’s condition, ovarian stimulation was initiated with FSH at 375 IU, LH at 75 IU, and GH at 9 mg. On the eighth day of stimulation, the LH dosage was increased to 150 IU based on the patient’s response. GH was started on Day 1 to support follicular recruitment from the onset due to severely diminished ovarian reserve.

The male partner, aged 33 years, had OAT. He received Coenzyme Q10 and multivitamins, and sperm freezing was conducted as part of the strategy to optimize sperm quality. The patient’s husband underwent a semen analysis, which showed OAT. After sperm washing, a resultant count of 1.04 million was achieved. Three embryos were successfully developed to the blastocyst stage and were frozen on Day 5 for future transfer.

In preparation for the frozen embryo transfer (FET), the patient was administered a combination of micronized progesterone at 800 mg daily, Progynova at 4 mg daily, Thromboaspilet at 80 mg twice daily, and low-molecular-weight heparin (LMWH) at 6000 units. Despite these interventions, pregnancy was not achieved during the FET cycle. The treatment was well-tolerated, and no adverse events were reported.

CASE 3:

A 39-year-old woman presented with a 2-year history of marriage and primary infertility. Laboratory assessment revealed an AMH level of 0.19 ng/mL, indicative of diminished ovarian reserve. She underwent ovarian stimulation using an agonist protocol, which included administration of FSH at 375 IU and LH at 75 IU. On the sixth day of stimulation, adjuvant GH at 9 mg was introduced. GH was initiated on Day 6 due to suboptimal early follicular growth, allowing for tailored timing to maximize response.

Her male partner, aged 41 years, had extreme OAT, requiring testicular sperm extraction (TESE), which yielded immotile sperm. Like Cases 1 and 2, he was treated with Coenzyme Q10 and multivitamins before TESE to potentially enhance sperm quality. The procedure yielded 2 vials of sperm, with a finding of immotile sperm (0% motility). To overcome this challenge, intracytoplasmic sperm injection (ICSI) with mechanical oocyte activation using calcium ionophore was performed to enhance fertilization potential. Following successful stimulation, a fresh embryo transfer at the blastocyst stage (Day 5) was performed. To support the luteal phase, the patient received micronized progesterone at 800 mg daily, Progynova at 4 mg daily, Thromboaspilet at 80 mg twice daily, and LMWH at 6000 units. Post-transfer testing showed an initial hCG result of 9.22 mIU/mL, followed by serial β-hCG levels declining to <2 mIU/mL by Day 14, confirming a biochemical pregnancy and early pregnancy loss.

CASE 4:

A 36-year-old woman presented with a 7-year history of marriage and primary infertility had an AMH level of 0.17 ng/mL, indicating diminished ovarian reserve. She had previously undergone an unsuccessful IVF attempt. Minimal stimulation was chosen using Clomiphene Citrate 50 mg twice daily and low-dose FSH (150 IU) due to poor ovarian reserve and a previous poor response to high-dose stimulation, aiming to optimize follicular quality while minimizing cost and risk of overstimulation. DHEA was administered once a day.

Ovarian stimulation resulted in the successful development and freezing of 7 Day-3 embryos. Her husband’s semen analysis indicated normozoospermia. Semen parameters were sperm concentration of 51 million/mL, progressive motility of 46%, and normal morphology of 6%. During the FET cycle, an artificial preparation protocol was followed. To enhance endometrial receptivity, the patient was given intravaginal Sildenafil at 25 mg twice daily and Pentoxifylline at 100 mg twice daily. Additionally, Enoxaparin at 0.4 mg was administered throughout the FET cycle to support implantation.

Following the embryo transfer, β-hCG testing showed a result of 296 mIU/mL. Pregnancy progressed to 12 weeks with fetal heartbeat confirmed by ultrasound, indicating a viable intrauterine pregnancy.

In all cases involving severe OAT, sperm washing, freezing, or TESE was employed to optimize sperm quality. Additionally, ICSI was performed in all cases to enhance fertilization rates by directly selecting and injecting the highest-quality sperm. These interventions aimed to mitigate the negative impact of male-factor infertility on embryo development.

Discussion

The management of primary infertility in cases involving both POI and male-factor infertility such as OAT was individualized. These 4 cases underscore the importance of personalized ovarian stimulation protocols, use of adjunctive therapies, and careful timing and selection of embryo transfer methods (Table 1). However, the lack of embryo grading and sperm DNA fragmentation data limits conclusions regarding embryo quality-related failures and potential contributions from paternal factors.

POI, often diagnosed by markedly low AMH levels, is a particularly challenging condition in reproductive medicine due to the limited ovarian reserve and subsequent poor response to stimulation protocols [9,10]. Low AMH levels not only correlate with fewer retrievable oocytes, but also often indicate poor oocyte quality, both of which contribute to reduced pregnancy success rates [11,12]. Studies indicate that co-treatment with growth hormone in antagonist protocols for patients with a history of poor response in previous IVF-ET cycles has not significantly improved pregnancy rates [13–15]. While GH was used in 3 out of 4 cases in this series, its inconsistent initiation timing (Day 6 in Cases 1 and 3, Day 8 in Case 2) and the absence of a dose-response relationship suggest that GH may not effectively overcome the fundamental issue of oocyte depletion in POI. This underscores the ongoing need for customized stimulation strategies, including increased gonadotropin dosages and potentially other adjuvant therapies, to better help women with low AMH levels.

The presence of POI in all 4 patients, as evidenced by low AMH levels, required aggressive ovarian stimulation strategies involving combinations of FSH, LH, and adjuvant GH to support follicular development. Previous studies have shown inconsistent benefits of GH in poor ovarian responders [16]. While some reports suggest improved oocyte quality, others indicate minimal impact on pregnancy rates [17]. Our findings align with this ambiguity, as GH was incorporated in multiple cases with mixed outcomes. In cases with POI, standard stimulation protocols often fail to yield an adequate number of mature oocytes, which decreases the chances of successful fertilization and pregnancy [18]. In each case, individualized adjustments were made to enhance the ovarian response. For example, in Case 2, the patient’s LH dosage was increased on the eighth day of stimulation to counteract the insufficient response to initial dosages. Such real-time adjustments underscore the importance of flexible protocols in POI cases. Although ICSI remains the criterion standard for overcoming sperm abnormalities, emerging technologies such as artificial sperm selection using AI are being investigated for future clinical applications.

Male-factor infertility further complicated each case, as each male partner exhibited varying degrees of OAT. OAT characterized by low sperm concentration, poor motility, and abnormal morphology, adds a layer of complexity to treatment, as these factors impair fertilization rates and potentially embryo quality [19]. Sperm washing and, in Case 3, testicular sperm extraction (TESE) were employed to optimize sperm quality. These methods aim to maximize the potential for fertilization despite poor initial sperm parameters, but their effectiveness can be limited by the extent of male infertility. For instance, in Case 3, despite TESE, the immotile sperm posed a challenge, resulting in limited success in achieving a viable pregnancy. The literature suggests that advanced sperm selection techniques, such as microfluidics and high-magnification ICSI, can improve fertilization outcomes in patients with severe OAT [20]. Furthermore, sperm DNA fragmentation testing has been proposed as an adjunct tool to identify sperm with better chromatin integrity, which could enhance embryo quality.

Beyond ovarian rejuvenation, novel interventions such as autologous mitochondrial transfer and platelet-rich plasma injections into the ovaries have been suggested as potential therapies for POI [21]. This limitation in sperm and oocyte quality highlights the need for advanced optimization techniques to improve outcomes in cases with severe infertility factors. Intracytoplasmic sperm injection (ICSI) was essential in these cases, as it allows the selection of individual sperm to be directly injected into the oocyte, bypassing motility issues. However, while ICSI can improve fertilization rates, it does not fully mitigate issues related to poor sperm morphology, which can still negatively impact embryo development [22]. Emerging research is exploring adjunctive techniques, such as sperm DNA fragmentation testing and high-magnification ICSI, which may enhance sperm selection for better fertilization outcomes in severe male infertility cases [22]. ICSI was utilized in all 4 cases to bypass sperm motility and morphology issues. In Cases 1 and 3, ICSI was critical due to severe OAT, ensuring successful fertilization despite poor semen parameters. However, fertilization rates varied, further emphasizing that ICSI does not fully overcome sperm-related embryo quality concerns.

The outcomes of these cases varied, with only 1 (Case 4) resulting in a successful pregnancy. The differential success rates could be attributed to several factors, including variations in patient response to ovarian stimulation, quality of the retrieved embryos, and overall endometrial receptivity. Notably, the sole success occurred in the case using minimal stimulation (Clomiphene + low-dose FSH) and Day-3 embryo transfer in a patient with a normozoospermic partner, suggesting that aggressive gonadotropin protocols may not necessarily benefit POI patients, particularly when male factors are not contributing. In Case 4, the successful pregnancy likely benefited from additional interventions aimed at enhancing endometrial receptivity, such as the use of intravaginal Sildenafil and Pentoxifylline, which may have improved uterine blood flow and implantation potential [23,24]. These adjuvant therapies, combined with anticoagulants like LMWH to support implantation [25], suggest that a comprehensive approach to endometrial preparation can improve outcomes in POI cases, although more extensive studies are needed to confirm these observations. Emerging therapies such as stem cell-based ovarian rejuvenation and mitochondrial replacement therapy are being explored for POI patients. While not yet widely available, these may offer potential breakthroughs in fertility preservation and enhancement.

For clinicians managing POI with concurrent male-factor infertility, key takeaways from these cases include the importance of individualized ovarian stimulation, the limited clinical benefit of GH despite its common use, and the critical role of endometrial receptivity enhancement. Addressing male infertility through optimized sperm selection and emerging sperm enhancement techniques is equally vital in improving fertility outcomes. While the presence of varying male-factor infertility (ranging from normozoospermia to OAT) adds complexity to these cases, it underscores the importance of addressing both ovarian and male factors in treatment protocols. Further research could focus on cases where male-factor infertility is controlled, such as normozoospermic patients or cases with OAT, to evaluate the impact of specific treatment protocols on pregnancy success rates in patients with low AMH. Larger case series or prospective studies with detailed reporting of embryo quality, sperm function, and adjunct use will help clarify the best treatment pathways for these complex infertility scenarios.

Conclusions

In conclusion, this case series reflects the challenges, complexities, and individualized approaches required to manage primary infertility in patients with POI and severe male-factor infertility. The presence of male-factor infertility was a significant contributor to treatment failures, highlighting the complexity of managing both POI and male infertility in tandem. Although outcomes remain unpredictable, these cases demonstrate that aggressive, flexible, and multi-faceted treatment protocols offer some potential for success. Enhanced ovarian stimulation, strategic sperm optimization, and meticulous endometrial preparation are key to improving fertility outcomes in such challenging cases. The variability in outcomes underscores that while advances in assisted reproductive technology are promising, personalized, adaptable approaches remain essential for addressing the intricate needs of each patient. Future research should explore questions such as: “Does mild stimulation benefit POI patients with normozoospermia?” and “What role does sperm DNA fragmentation play in treatment outcomes for severe male infertility?” In future studies, we recommend controlling for male-factor infertility (eg, normozoospermia or OAT) to better evaluate the effectiveness of ovarian stimulation protocols and adjunctive therapies. This will provide clearer insights into the optimal approach for POI patients with low AMH. For clinicians managing POI with concurrent male-factor infertility, key takeaways from these cases include the importance of individualized ovarian stimulation, the limitations of GH in improving success rates, and the critical role of endometrial receptivity enhancement. Larger case series or controlled trials are needed to refine treatment protocols and evaluate the effectiveness of adjunct therapies in POI patients.