Updated June 2019: CHR is currently recruiting participants for two clinical trials on ovarian rejuvenation using platelet-rich plasma (PRP). One study is for patients with a diagnosis of premature ovarian insufficiency (POI) and the other is for women over 40 with age-related decline in ovarian reserve. If you are interested in participating, please contact us online or call us at 212-994-4400.
Ovarian rejuvenation has been a topic in these pages a few times before. Discussing the subject must always start with a definition of what the term really means. Since ovaries age as we get older, it is not surprising that, at a time when anti-aging medicine is quickly gaining popularity, rejuvenation of ovaries has also become an increasingly popular subject. There is, however, one big difference between ovarian aging and the aging of pretty much any other organ in our bodies: No other organ contains a finite number of eggs or a functional equivalent that declines with advancing age. In other words, the ovary not only undergoes similar functional and structural aging as other organs but, in parallel, also loses eggs, and those, at present, are still irreplaceable.
Ovarian rejuvenation, therefore, is able to address only the basic aging process that ovaries, like any other organ, are subjected to but cannot restitute egg numbers by creating new eggs.
This is important to understand because under this definition of “rejuvenation,” CHR has for many years been rejuvenating ovaries by improving numbers and quality of eggs ovaries produce with androgen (i.e., DHEA or testosterone) or human growth hormone (HGH) supplementation.
This is, however, not the kind of “rejuvenation” Internet and media have been talking about because this term has been to a degree incorrectly adopted by including what is better called mechanical ovarian rejuvenation because, in contrast to above referred to medical treatments of ovaries, these treatments require invasive procedures into ovaries. The concept was first applied ca. four years ago in women with premature ovarian failure (POF), also called primary ovarian insufficiency (POI), by Japanese colleagues and colleagues from Stanford University in California, when they surgically removed ovarian tissue, and then in vitro (in the laboratory) fragmented the tissue to disrupt signaling through the so-called Hippo signaling pathway before treating the tissue with drugs that stimulated the so-called Akt signaling pathway (Kawamura et al., PNAS 2013;110(43):17474-17479). Hippo disruption leads to increased expression of downstream growth factors, and improved follicle growth, which is further augmented through Akt stimulation. Once so treated, the ovarian tissue was surgically re-implanted into the patient with the plan either to undergo in vitro fertilization (IVF) or attempt spontaneous conception. Kawamura et al in above quoted manuscript reported one pregnancy from IVF. Worldwide a handful of pregnancies have since been reported utilizing this technique in POF/POI patients.
Though manipulation of Hippo and Akt signaling pathways appeared to represent intriguing new potential technologies, CHR investigators considered the need for two surgical interventions for an obviously low yield procedure as too invasive and, therefore, started exploring alternatives. One such alternative because of its relative simplicity, was the idea that ovarian tissue did not have to be removed to be disrupted but can, likely also be achieved in vivo (in the body). Approximately one year ago, CHR, therefore, started in highly selected POF/POI patients who had failed to respond with all standard treatments to offer what we have come to call “ovarian (needle) piercing.”
This experimental procedure basically mimicked an egg retrieval in that, with the patient under intravenous sedation by an anesthesiologist, ovaries were repeatedly needled in hope of achieving ovarian tissue disruption and, therefore, potentially also disruption of Hippo-signaling, and desired downstream effects on follicle growth and development. Still in single digits, the number of such attempts at CHR is too small to judge the effectiveness of such an approach. So-far only one patient achieved follicle growth in a subsequent ovarian stimulation, though did not achieve pregnancy. As currently performed, this procedure, therefore, likely, at best will yield only rare successes.
CHR, therefore, decided to go on to a potential next step, and, in analogy with above noted Japanese and California colleagues, combine mechanical ovarian piercing (i.e., disruption of the Hippo pathway) with potentially helpful medical treatment. In addition to Hippo pathway disruption, our colleagues also treated the ovarian tissue they had surgically removed with stimulators of the Akt signaling pathway, which since a groundbreaking paper demonstrated that deletion of Pten causing premature and explosive activation of primordial follicles [Reddy et al, Science 2008;319(5863):611-613], was recognized to enhance recruitment of primordial follicles. The Akt signaling pathway is, however, frequently deregulated in quite a number of cancers. Injection of Akt-inducing biological substances was, therefore, considered too risky since infertile women are already at increased risk for ovarian cancer.
CHR investigators, therefore, started to explore other options with potential to enhance Hippo disruption during ovarian piercing, and a search of the literature lead us to the rapidly expanding use of autologous (the patient’s own) so-called platelet rich plasma (PRP) in a number of medical specialties.
PRP is extracted from the peripheral blood of patients and represents a small fraction of the blood’s plasma. It is relatively simple to extract in a quick centrifugation process and represents ca. 10 percent of the initial blood volume. Ten milliliters (ml) of blood, therefore, will yield ca. one ml of PRP, a perfectly adequate volume for a single treatment.
While initially quite controversial when PRP was first introduced as treatment for injured professional athletes, injections of autologous PRP has since become routine treatment in orthopedics, in certain autoimmune conditions and in dermatology. After a Greek IVF center claimed through the lay press successful pregnancies in POF/POI patients after ovarian treatment with PRP, a number of U.S. IVF clinics started offering this treatment clinically, using the term “ovarian rejuvenation.” One California-based clinical trial is registered at ClinicalTrials.gov as recruiting, under that term.
A detailed literature search, however, revealed not a single published study using PRP in the treatment of POF/POI or any other ovarian condition in humans. The only published manuscript involving PRP in any ovarian experiment demonstrated a protective effect of PRP on an experimentally-induced ischemia/reperfusion injury in rat ovaries [Bakacak et al., Gynecol Obstet Invest 2016;81(3):225-231], thereby supporting, also reported in other medical specialties, an anti-inflammatory and pro-healing effect of PRP. Along the same lines, two recently published studies also suggested that PRP may be effective in treating chronic endometritis and endometrial adhesions (Asherman’s syndrome).
PRP contains a multitude of growth factors and cytokines, which are generally held responsible for observed anti-inflammatory and pro-healing effects. The hypothesis of CHR’s upcoming PRP study, therefore, will be that these growth factors and cytokines may be able to augment the tissue disrupting effects of ovarian piercing, thereby hopefully inducing recruitment of remaining follicles, which previously were unresponsive. Since even menopausal women still do have primordial follicles, even limited results may produce small numbers of potentially retrievable eggs. Moreover, since POF/POA patients are usually still relatively young, even one or two eggs will offer them still decent pregnancy chances.
This study will not require randomization. In other words, every qualified patient will receive the treatment because every patient will serve as her own control. This will be achieved by treating only one of each patient’s ovaries, while the other one will serve as control. Which ovary will be treated, will be determined by randomization.
The study will be conducted in collaboration with Andrea Weghofer, MD, PhD, MS, MBA from the Vienna Medical University in Austria, who has been a collaborator of CHR for many years after spending initially a full year in a combined fellowship between CHR and Yale University. She in April will come to CHR to help get the project off the ground. The study still has to go through approval of CHR’s Institutional Review Board (IRB) and registration; but considering that it only involves injection of very small amounts of patients’ own plasma, already widely practiced in other specialties, we do not expect difficulties in obtaining approval.
Preparation of PRP and treatments with PRP will be free of charge. Since intravenous sedation by an anesthesiologist will be required for the intra-ovarian injections, reduced anesthesia and operating room charges, will, however, apply. In addition, agreement to undergo at least one ovarian stimulation with routine gonadotropins approximately two weeks following ovarian piercing will be required to participate in the trial. Study participants will be responsible for regular charges for consultations, testing and all cycle-related procedures, including cancellation charges.
This study is currently recruiting participants. If you are interested to potentially participate in this trial or if you know somebody who might be interested, please write to us or call us at 1 212-994-4400. We hope to initiate this study by April 1, 2018.
This is a part of the February 2018 CHR VOICE.
Norbert Gleicher, MD, leads CHR’s clinical and research efforts as Medical Director and Chief Scientist. A world-renowned specialist in reproductive endocrinology, Dr. Gleicher has published hundreds of peer-reviewed papers and lectured globally while keeping an active clinical career focused on ovarian aging, immunological issues and other difficult cases of infertility.
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