“Forever fertile”: ovarian tissue cryopreservation for an extended reproductive lifespan

Abstract

The global decline in birth rates highlights the need for effective fertility preservation strategies. Even though oocyte cryopreservation is a well-established technique in cancer patients and is increasingly requested for elective fertility preservation, its success is limited by age at freezing and restoration of ovarian activity is not provided. Ovarian tissue cryopreservation is emerging as a promising alternative for both fertility preservation and reproductive lifespan extension. Unlike oocyte cryopreservation, ovarian tissue cryopreservation restores endocrine function, potentially delaying menopause and reducing associated health risks. Although concerns exist regarding graft longevity and surgical invasiveness, recent advancements—such as improved cryopreservation techniques, neovascularization strategies, and minimally invasive approaches—enhance its feasibility. Additionally, ovarian tissue cryopreservation allows for spontaneous conception, reducing the need for assisted reproductive technologies. As demand for reproductive longevity increases, the medical community must address ethical and regulatory implications while refining clinical applications. Integrating ovarian tissue cryopreservation into elective fertility preservation can provide women with more reproductive choices, aligning with advances in longevity medicine. Future research should focus on optimizing graft survival and assessing long-term health outcomes of delayed menopause to fully unlock the potential of ovarian tissue cryopreservation.

Introduction

The global trend towards declining birth rates is impossible to ignore: by 2100, 93% of all countries will have a total fertility rate below the replacement level of 2.1 children per woman, while most higher-income countries will reach that level 50 years earlier [1]. Over the last two decades, the reproductive medicine community has been very vocal about the need for fertility preservation when facing gonadotoxic therapies. Fertility preservation counseling has thus become a gold standard step in the diagnostic and therapeutic pathways of most oncological and non-oncological diseases [2]. This alone represents a revolution in the field, introducing the theme of preserving fertility instead of treating infertility, but it is not enough to slow the tide of reduced birth rates worldwide. Indeed, while some diseases or therapies may damage ovarian reserve, the primary factors responsible for declining birth rates are the sociocultural conditions prompting delayed childbearing [3] and the increasing impact of pollutants found in the air we breathe and the food we eat [4]. In a way, these two factors may be considered gonadotoxic agents impacting the entire population. The whole society should come together to tackle these complex issues as soon as possible, while reproductive medicine specialists should try to provide answers to a growing number of women seeking strategies to effectively preserve their future fertility.

Extended reproductive lifespan: would this be a need for the women of the future?

While society and politics fail to keep pace with the evolving demands of modern life—where individuals increasingly pursue education and careers—the result is that women increasingly desire and seek reproductive medical assistance to achieve pregnancy at an older age. For example, in Italy—where, for the first time since national unification, the number of births has fallen below the 400,000 threshold—births among women over the age of 40 are steadily increasing, accounting for more than 10% of all births in 2023 [5]. Notably, this upward trend is also observed in births among women over 45, an age at which spontaneous pregnancies are exceptionally rare. Egg donation is currently the most used technique; however, fertility preservation at a younger age could become an area of significant interest for this population. Considering the increasing disease-free lifespan in Western populations and the growing interest in longevity medicine, it is plausible that the desire for reproduction well beyond the age of 50 may emerge in the future. Do we have safe and effective solutions to offer? Are current fertility preservation techniques equipped to meet this challenge?

Elective oocyte cryopreservation as the main strategy for preserving fertility

Oocyte cryopreservation, initially established in the context of infertility therapies and later adopted as an urgent oncofertility strategy [6], is frequently represented in the news, with an increasing number of voices advocating for a more widespread use of elective egg freezing. It is important for this topic to acquire front-page status, but the discussion is usually centered on costs or usage rates, overlooking one pivotal question: what is the actual efficiency of the procedure? Or, in other words, what are we preserving?

Mature oocyte cryopreservation has an estimated success rate of 5%/oocyte [7], but it is reduced dramatically with age, as the number of aneuploidies increases [8]. The available literature shows how cryopreserving 12–13 oocytes between 30 and 35 years may give our patients a chance of one live birth which is approximately 60% similar to the one she would have if she tried to conceive spontaneously for 1 year at the age of cryopreservation [7, 9, 10]. Of course, the number increases if the patient desires more than one pregnancy, making it necessary to undergo more than one cycle of ovarian stimulation to accumulate oocytes. Oocytes may be used also in case of subsequent ovarian insufficiency or menopause, but they do not restore ovarian endocrine function, so an artificial endometrial preparation is needed, increasing the risk of hypertensive disorders of pregnancy [11] in women already at risk due to advanced maternal age. Lastly, since the cryopreserved eggs must be fertilized with ICSI and then transferred in the uterus, the chances of a live birth/transfer are around 30% only, as fertility procedures success rates did not increase in the last decade [12].

Ovarian tissue cryopreservation: an underutilized technique

Ovarian tissue cryopreservation was first introduced in the 1990 s to address the need for fertility preservation methods in prepubertal girls and in those requiring urgent oncological therapy. The technique was pioneered by Roger Gosden’s laboratory [13], the first transplantation procedure was performed in 1999 by Kutluk Oktay’s team [14], and the first live birth was obtained in 2004 in Belgium by Jacques Donnez [15]. The procedure involves laparoscopic surgery to retrieve an ovarian biopsy, ranging from one-third of the ovary to the entire ovary. The ovarian cortex is then cut into strips, dehydrated in a cryoprotectant solution, and cryopreserved, typically using the slow freezing technique [16]. The cortical strips can then be transplanted back into an orthotopic site (the remaining ovary) or heterotopic site (such as the pelvic side wall, subcutaneously or intramuscularly). To date, approximately 200 babies are born after cryopreserved ovarian tissue transplantation [16] and the procedure is no longer considered experimental [17]. Outside cancer patients, this procedure’s potential was clear in women with premature ovarian insufficiency (POI) [18]. In 2005, the first successful case of fresh ovarian tissue donation in monozygotic twins was reported [19], followed by small but promising case series [20, 21].

The real game changer of ovarian tissue cryopreservation is that, in addition to offering an estimated 21% chance of live birth through spontaneous conception and 33% through ART [22], it is the only method that provides restoration of endocrine gonadal function.

Despite these premises, ovarian tissue cryopreservation has never been really introduced in clinical practice as an option for elective fertility preservation with the aim of not only achieving a pregnancy in the future, but to postpone menopause [23] (see Table 1).

Table 1.

Pros and cons of oocyte cryopreservation versus ovarian tissue cryopreservation

	Pros	Cons
Oocyte cryopreservation	Well-established technique	No restoration of ovarian endocrine function
	Widespread availability of the technique	No applicability in prepubertal girls
	Immediate availability of eggs for subsequent IVF cycles	Demand of high number of oocyte to achieve subsequent live birth
		Ovarian stimulation with gonadotropins > 10 days
		Reliance on IVF techniques
Ovarian tissue cryopreservation	Restoration of ovarian endocrine function	Limited availability of the technique
	Delay of menopause	More invasive procedure (laparoscopy versus pick up)
	Possibility of more transplants	Removal of part of the ovary
	Reduced need for ovarian stimulation	Unplanned pregnancy at older age after orthotopic transplant for hormonal replacement purpose
	Possibility of spontaneous pregnancy
	Applicability in prepubertal girls

There are three main reasons for the underutilization of the technique in this setting: the first experiences showed a reduced function of the grafts; the need of undergoing at least two surgical procedures labels the option as too invasive; there are scarce data regarding benefits on climacteric symptoms and risks.

Regarding the first point, literature shows how 72% of women re-acquire ovarian function (as regular menstruation and compatible hormonal levels) with a median time of 18 weeks after transplantation and maintain it for a median time of 2.5 years, range 0.7–5 years [16]. This time may be optimal for those searching for a pregnancy but seems largely insufficient to justify a procedure for endocrine function restoration only.

However, it has to be considered that the results of the first cases of ovarian tissue transplantation were crippled by the overactivation of primordial follicles due to ischemia and the subsequent early exhaustion of the transplanted cortical pieces [24]. A better knowledge of the molecular pathways involved in this process, through effective collaboration between basic and clinical research, is pivotal in improving success and duration of endocrine function restoration. For example, a case series showed improved graft longevity in a small cohort, treated with perioperative estrogens and aspirin, when cortical strips were sutured onto a neovascularizing extracellular matrix scaffold before being transplanted using robot-assisted laparoscopy [25]. Moreover, most of the data are based on urgent procedures at the time of cancer diagnosis and include both pre- and postpubertal patients, as well as patients with low ovarian reserve, so it is reasonable to expect even better results in selected young women undergoing an elective procedure. The laboratory expertise also plays a role: the cryopreservation procedure is technically challenging, as it requires trained staff and a specifically equipped laboratory. It is important to note that we have evidence that a hub and spoke model is feasible, as an overnight transport does not damage the tissue [26].

Regarding the surgical procedure, the primary sources of doubt and fear are twofold: the invasiveness and inherent surgical risks, and the potential damage to the ovarian reserve when operating on the ovary.

A laparoscopic surgery is needed at the time of the biopsy and, in most cases, at transplantation. Although the procedure is considered minimally invasive, it still involves potential risks such as infection, bleeding, or damage to the surrounding tissues. These risks cannot be completely avoided, but published cohorts show minimal complications: 6% risk of surgical incision site infection [27] and 0.6% risk of re-laparoscopy for hemostasis [28]. It is worth mentioning that these data are mostly based on cohorts of pediatric patients affected by neoplasms, therefore more at risk of complications if compared to healthy young women. To further minimize the invasiveness of the procedure, the use of a transvaginal approach was anecdotally suggested [29], but benefits and risks, compared to traditional laparoscopic approach, are still to be ascertained. Surgery and anesthesia risks may be greater in case of transplantation at an older age. If the main outcome is menopause reversal and not a pregnancy, the cortical strips can be placed subcutaneously, avoiding abdominal surgery and the risk of unplanned pregnancies. This option is successful in restoring endocrine function and can be done under local anesthesia, and the tissue can be easily removed if issues arise [30]. Orthotopic and heterotopic autologous ovarian tissue transplants demonstrated similar endocrine function restoration rates and longevity; therefore, heterotopic transplant should be preferred in women who do not desire to conceive [31].

Another concern is that ovarian surgery itself may cause iatrogenic damage to the remaining ovary. This risk is largely mitigated by the surgeon’s expertise: suturing, rather than surgical energy, should be used for hemostasis to avoid damage in the remaining tissue [32]. However, it is undeniable that a portion of ovarian tissue, varying from 1/4 to one ovary, is removed.

To date, no clinical study is available in literature to evaluate modifications of age at menopause after ovarian tissue cryopreservation in a cohort of healthy patients (i.e., patients who did not receive gonadotoxic cancer treatments).

If we consider the data on monolateral ovariectomies, it appears like the younger the age at ovarian surgery, the bigger the risk of anticipating menopause age. Thomas-Teinturier and colleagues reported on age at menopause after unilateral ovariectomy for childhood cancer and found an anticipation of 7 years compared to controls, at a median age of 44 years [33]; however, it has to be noted that this was a population of cancer survivors who also received gonadotoxic treatments. Rosendahl and colleagues studied the effect of unilateral ovariectomies in adult patients finding an age of menopause anticipated of 1.8 years (49.5 versus 51.3 years), with younger age at oophorectomy linked to younger age at menopause [34]. Other studies confirmed a slight, but not clinically significant, decrease in the age at menopause that stayed well above the cut-off for premature ovarian insufficiency [35], leading to hypothesized compensatory mechanisms in the other ovary.

When performing elective ovarian tissue cryopreservation in adults, there is usually no need to remove a whole ovary, since 1/4 to 1/3 is enough to guarantee endocrine function in the future [23]. The lack of specific safety data arises from the fact that this technique is not yet employed in clinical practice for elective fertility preservation in healthy women, and the same holds true for efficacy data. To date, no clinical studies are available to compare the effects of ovarian tissue transplantation versus hormonal replacement therapy (HRT) on climacteric symptoms. Moreover, there is a lack of data regarding the probability of developing a new peri-menopause phase, with its possible specific issues (for example, menstrual irregularities, menorrhagia, and effects of breast cancer risk), once the transplanted tissue is extinguishing its activity. Later natural menopause is associated with reduced cardiovascular risk but increased risks of breast, ovarian, and endometrial cancers. Overall, each additional year of delayed menopause has been linked to a 2% reduction in age-adjusted mortality, suggesting a net benefit in lifespan [36]. It is plausible that women who undergo ovarian tissue transplantation and experience later menopause may see similar benefits. However, it is also possible that longer lifespan in naturally late-menopausal women reflects underlying differences in cellular aging, which may not apply to transplant recipients. When we look at women using HRT, benefits on biological aging [37], overall [38] and cardiovascular [39] mortality were reported when therapy is initiated within the first 10 years after menopause.

Extended reproductive lifespan: why ovarian tissue cryopreservation will be the first choice

Preserving fertility through ovarian tissue cryopreservation, especially as the technique is being perfected, offers a significant advantage over conventional oocyte cryopreservation, restoring the ovarian environment and prolonging the reproductive lifespan. Moreover, it does not hinder the chance of conceiving in the meanwhile, as a woman does not require both ovaries to conceive at a young age. Freezing an entire ovary—or even a portion of it—allows for the preservation of a substantially higher number of oocytes compared to standard egg freezing techniques. Ovarian transplantation, restoring the hormonal environment typical of the reproductive years, provides substantial psychological and physical benefits. Menopause is associated with an increased risk of various health conditions; thus, extending the reproductive lifespan could potentially offer far-reaching health advantages beyond fertility alone (see Fig. 1). However, the potential advantages reported in Fig. 1 are extrapolated from hormonal replacement therapy (HRT) research; therefore, they must be confirmed with robust data in the ovarian transplantation setting, and they must be carefully weighed against possible risks, such as an increased likelihood of breast cancer.

Fig. 1.

Possible benefits of ovarian tissue cryopreservation and subsequent transplantation at different ages. Ovarian tissue cryopreservation should be performed before the age of 35 in order to obtain good-quality samples. Orthotopic transplantation may be performed in women over 40 years old, compensating their physiological reduction of fertility and allowing spontaneous conception. However, assisted reproductive technologies (ART) would likely play an important role in order to improve the chance of pregnancy during the limited lifespan of the graft. Moreover, women approaching menopause may undergo multiple heterotopic transplants in order to delay it. Based on hormonal replacement therapy (HRT) effects, possible benefits of extended ovarian hormonal activity are displayed, nonetheless prospective studies are necessary to confirm this assumption

An important aspect to highlight is that ovarian transplantation, unlike oocyte cryopreservation, offers the possibility of spontaneous conception, especially in women older than 40 years. While assisted reproductive technologies (ART) would still be relevant due to the limited lifespan of grafts and regulatory constraints, the ability to conceive naturally introduces new considerations. Of particular concern is that spontaneous conception may occur with less medical oversight and counseling, which is particularly important given the increased risks associated with pregnancy at an advanced maternal age. The data we have on pregnancies after ovarian tissue transplantation are mostly in relatively young cancer survivors [16]. Even if pregnancies following elective ovarian tissue cryopreservation were likely to result from similarly young oocytes (an assumption that is not obvious, given that the remaining tissue could also produce oocytes, at least in women aged 45 or younger), we must not overlook the well-documented obstetric risks associated with advanced maternal age, regardless of oocyte age [40, 41]. From an obstetric perspective, such an unregulated scenario may seem concerning, if not dystopian. However, if we fail to proactively address and regulate these emerging advancements, we risk merely reacting to them—potentially facing unintended consequences rather than shaping their responsible evidence-based integration into clinical practice.

Conclusions

With the steady increase of the age at independent adulthood, first pregnancy and retirement, there is growing demand for elective fertility preservation and maintenance of ovarian function with age. This is fitting perfectly in the equally growing pursuit of longevity and longevity-correlated research [42]. Patients are already asking, and will ask even more in the future, for strategies to prolong their reproductive life and to avoid hypoestrogenism adverse effects, and we should be able to counsel them about the different strategies, with evidence-based information regarding their expected benefits and possible limitations or side effects. So far, the role of ovarian tissue cryopreservation has been considered marginal, mainly for its perceived invasiveness, but as an established fertility preservation option it should be discussed and proposed along with oocytes cryopreservation. Naturally, we cannot communicate what we do not yet know, and the lack of long-term safety and efficacy data in this population must be clearly conveyed during counseling. Such evidence will only become available if it is collected rigorously and transparently through well-designed research protocols. While we must wait to understand if it could become common practice, we also acknowledge that the untapped potential seems almost unlimited: a stochastic model predicted an impressive delay in menopause of 23 to 31 years if a woman with a median ovarian reserve had cryopreserved 25% of the cortex and then underwent three to six transplantation procedures, each with a 40% follicle survival [43]. Currently no other strategy has the potential to offer comparable results. While the idea of “forever fertility” may seem dystopian and unappealing to most, the ethical and responsible use of existing technologies—guided by shared decision-making with the woman and supported by rigorous long-term risk assessment—can enhance reproductive autonomy and empower informed choices.

Author contribution

C.M. and A.L.M. conceived the idea for the paper and contributed to design, drafting, revision, and final approval of the article. C.S. contributed to writing, revision, and final approval of the article.

Funding

The authors did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Data availability

No new data were generated or analyzed in support of this paper.

Declarations

Competing interests

The authors declare no competing interests.