Evaluation of safety, feasibility and efficacy of intra-ovarian transplantation of autologous adipose derived mesenchymal stromal cells in idiopathic premature ovarian failure patients: non-randomized clinical trial, phase I, first in human

Authors: M. Mashayekhi et al. (published Jan 6, 2021)

This was a first‑in‑human, phase I clinical trial testing whether a patient’s own fat‑derived stem cells (called adipose‑derived stromal cells or ADSCs) can be safely placed into an ovary and whether this might help women with idiopathic premature ovarian failure (POF). POF means the ovaries stop working before age 40 and affects about 1–2% of women of reproductive age. Current fertility options are limited (often donor eggs). Stem cells can create a regenerative environment and might support ovarian tissue and remaining eggs.

Key practical points:

• Safety: The main goal was to check short‑ and medium‑term safety. No serious early or late complications were observed during 12 months of follow‑up.
• Signs of activity: Some patients (4 of 9) had menstrual periods return for months after treatment, and 4 patients showed drops in a key hormone (FSH) that can indicate improved ovarian activity. Other measures of ovarian reserve (AMH and antral follicle count) were variable and did not show clear improvement.
• Small, early study: This is encouraging but exploratory. Larger, randomized studies are needed before this becomes a standard option.

Relevance for stem cell banking and regenerative medicine:

• ADSCs are attractive for future autologous therapies because they can be collected in large numbers from a simple fat biopsy, expanded under GMP conditions, and returned to the same person with low risk of immune rejection.
• Banking adipose tissue (or expanded ADSCs) today could preserve material for later regenerative treatments aimed at ovarian insufficiency or other age‑related tissue repair, but clinical benefit is not yet proven.

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Background: Premature ovarian failure (POF) is loss of ovarian function before 40 years. Animal studies and a few human reports suggest mesenchymal stem cells may help restore ovarian activity. The study assessed safety, feasibility, and initial signs of efficacy of transplanting each patient’s own ADSCs directly into one ovary.

Methods: Non‑randomized phase I trial. Nine women (age 20–39) with confirmed idiopathic POF were assigned to one of three cell doses: 5 × 10^6, 10 × 10^6, or 15 × 10^6 ADSCs (three patients per dose). Cells were harvested from sub‑abdominal fat, processed in a GMP facility, and injected into one ovary under ultrasound guidance (some by laparoscopy when needed). Follow‑up occurred at 24 hours; weeks 1 and 2; and months 1, 2, 3, 6, and 12. Primary outcome: safety. Secondary outcomes: return of menstruation, FSH and AMH hormone levels, antral follicle count (AFC), ovarian volume, and dose effects.

Results: No early or late serious adverse events were reported during 12 months of follow‑up (no bacteremia, sepsis, pelvic infection, ovarian abscess, or tumors observed by exam and ultrasound). Four of nine patients resumed menstrual bleeding for several months (two in the 15 × 10^6 group at 2 months; one in the 5 × 10^6 group and one in the 10 × 10^6 group at 1 month). Serum FSH fell to below 25 IU/L in four patients; in two patients the decline remained through 12 months. AMH, AFC, and ovarian volume showed variable changes without significant differences between dose groups (p > 0.05). No statistically significant differences in outcomes between the three dose groups were found.

Conclusions: Intra‑ovarian transplantation of autologous ADSCs was feasible and appeared safe over 12 months in this small group. Some patients had menstrual return and FSH reductions, but results were inconsistent. Larger randomized trials are needed.

Trial registration: ClinicalTrials.gov NCT02603744.

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• What is POF? Premature ovarian failure (also called primary ovarian insufficiency) is when ovaries stop functioning before age 40. Women may have prolonged absence of periods (amenorrhea) and high FSH levels (>25 IU/L on two occasions), and infertility is common.
• Why stem cells? Research shows adult ovaries may contain stem‑like germ cells and that the ovarian environment (the “niche”) matters for egg development. Mesenchymal stromal/stem cells (MSCs) from bone marrow, endometrium, placenta, or fat have been shown in animals to help repair ovarian tissue after chemotherapy, possibly by secreting growth factors and improving blood supply and local signals. ADSCs (fat‑derived MSCs) are easy to collect in large numbers with a minimally invasive procedure and can be used in the same person (autologous), lowering immune risks.

How this links to stem cell banking: banking adipose tissue or expanded ADSCs could preserve a patient’s own regenerative cells for future therapies targeting ovarian function or other age‑related repairs.

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• Participants: 9 women, 20–39 years old, with confirmed idiopathic POF (FSH ≥ 25 IU/L on two occasions). All had at least one year of amenorrhea prior to enrollment.
• Cell harvest and preparation: ~50 mL of sub‑abdominal fat was liposuctioned. Cells were isolated, digested with collagenase, cultured under GMP conditions, and checked by flow cytometry for MSC markers (CD105, CD90, CD73). Viability was 85–90% in final suspensions.
• Transplantation: Each patient received a 2 mL suspension containing the assigned dose (5, 10, or 15 million cells) injected into one ovary under transvaginal ultrasound guidance (or laparoscopy in two difficult cases). The contralateral ovary was left untouched as a safety measure.
• Follow‑up and outcomes: Safety checks at 24 hours and 1–2 weeks, then at months 1, 2, 3, 6, and 12. Measured FSH, AMH, AFC (ultrasound), ovary volume, and monitoring for infections, abscesses, or neoplasms. Statistical analysis used one‑way ANOVA to compare dose groups; p < 0.05 considered significant.

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• Enrollment: 50 women were screened; 9 completed the study and received treatment (3 per dose group).
• Safety: No early or late serious adverse events detected during 12 months (no bacteremia, sepsis, pelvic infection, ovarian abscess, or tumors by exam and ultrasound).
• Menstruation: 4 of 9 patients had return of menstrual bleeding for months after treatment:
• 15 × 10^6 group: 2 patients had menstruation beginning at 2 months (one continued to month 5, the other had bleeding in months 2 and 4).
• 5 × 10^6 and 10 × 10^6 groups: one patient in each group resumed menstruation at 1 month, continued for 7–8 months in those cases.

Differences between dose groups were not statistically significant (p > 0.05).

• FSH hormone: Serum FSH fell to < 25 IU/L in 4 patients at various time points (weeks 1–2, month 1, month 2). In two patients the decline remained through 12 months. There were no statistically significant differences between dose groups (p > 0.05). The 5 × 10^6 group showed the lowest mean FSH at 1 year compared with baseline (mean ± SE: 21.45 ± 15.55 vs. 68.3 ± 24.5), but this was not statistically significant (p = 0.631).
• AMH, AFC, ovarian volume: These measures were variable with no clear or consistent increase across patients and no statistically significant differences between dose groups (p > 0.05).

Table and figure data (from the paper) summarize these numeric results and time courses for FSH, AMH, AFC, and ovary volume.

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• Safety: This small, carefully monitored study suggests that injecting a woman’s own ADSCs into an ovary is feasible and did not cause short‑term safety problems during 12 months of follow‑up.
• Signals of effect: Menstrual return in 4 of 9 patients and sustained FSH decline in 2 patients suggest possible biological activity in some cases, but effects were inconsistent. Key ovarian reserve measures (AMH and AFC) did not show clear improvement.
• Possible mechanisms: ADSCs probably act via paracrine (secreted growth factors and cytokines) and niche‑modifying effects rather than by turning into eggs themselves. Animal studies show ADSCs can raise factors like VEGF and TGF‑β that support blood supply and local cell survival. They may activate existing ovarian stem/progenitor cells or improve the environment for remaining follicles.
• Dose: No clear dose–response was seen between 5, 10, and 15 million cells. The authors suggest the lower dose (5 × 10^6) might be cost‑effective and could be repeated or given bilaterally in future trials, but this requires testing.
• Limitations: Very small sample (n=9), non‑randomized, no placebo control, and only one ovary treated per patient. Follow‑up of 12 months is reassuring but not enough to fully exclude rare long‑term risks (e.g., tumor formation). Larger randomized controlled trials (RCTs) are needed to confirm both safety and efficacy.

Clinical context and prior reports: Prior animal studies and rare human reports (e.g., autologous bone marrow stem cell transplants with reports of menstrual recovery and at least one live birth) support the idea but are not definitive. This study adds first‑in‑human phase I data specifically with adipose‑derived MSCs.

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• Why adipose tissue banking could matter: Fat is an accessible and rich source of MSCs. Banking adipose tissue or cryopreserved ADSCs while a woman is younger may preserve autologous cells that could later be used to treat ovarian insufficiency or other age‑related tissue problems.
• Autologous advantage: Using a person’s own cells avoids immune rejection and many regulatory hurdles associated with donor cells.
• Not yet standard care: Despite encouraging early safety data and some biological signals, ADSC intra‑ovarian therapy is experimental. Anyone considering adipose or cell banking should understand that clinical benefits for ovarian rejuvenation are unproven and require larger trials.
• Future directions: Well‑designed randomized controlled trials, longer follow‑up (years), bilateral ovarian treatment strategies, and standardized cell‑processing protocols are needed to determine whether this approach can reliably restore fertility or delay ovarian aging.

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• In this small phase I trial (n=9), intra‑ovarian autologous ADSC transplantation was feasible and showed no serious safety issues over 12 months.
• Some patients showed menstrual resumption and lowered FSH levels, but results were inconsistent and AMH/AFC did not show clear improvement.
• Larger randomized studies with longer follow‑up are required before clinical use can be recommended. Banking adipose tissue or ADSCs could be useful for future regenerative options, but expectations should be cautious.

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• Clinical trial registration: NCT02603744 (phase I intra‑ovarian ADSC study).
• Animal evidence that ADSCs improve chemotherapy‑induced ovarian failure: Sun M et al., Stem Cell Res Ther. 2013;4:80.
• First reports of autologous bone marrow stem cells for idiopathic POF with menstrual recovery and a live birth: Edessy M et al., Acta Med Int. 2016;3:19; Gupta S et al., J Hum Reprod Sci. 2018;11:125.
• ESC/ESHRE guidelines and diagnostic criteria for premature ovarian insufficiency: ESHRE guideline (Webber L et al., Hum Reprod. 2016;31:926–37).

(Full reference list is available in the original publication.)

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This study is an early safety and feasibility trial and should be viewed as preliminary. Patients interested in experimental stem‑cell options for POF should consult a specialist, consider clinical trial enrollment, and be aware that adipose/stem cell banking is an option to preserve autologous material for future research and potential therapies — but current evidence of benefit for ovarian rejuvenation is still limited.