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The Scientific and Cultural Journey to Ovarian Rejuvenation: Background, Barriers, and Beyond the Biological Clock

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The Scientific and Cultural Journey to Ovarian Rejuvenation: Background, Barriers, and Beyond the Biological Clock

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Female age has been known to define reproductive outcome since antiquity; attempts to improve ovarian function may be considered against a sociocultural landscape that foreshadows current practice. Ancient writs heralded the unlikely event of an older woman conceiving as nothing less than miraculous. Always deeply personal and sometimes dynastically pivotal, the goal of achieving pregnancy often engaged elite healers or revered clerics for help. The sorrow of defeat became a potent motif of barrenness or miscarriage lamented in art, music, and literature. Less well known is that rejuvenation practices from the 1900s were not confined to gynecology, as older men also eagerly pursued methods to turn back their biological clock. This interest coalesced within the nascent field of endocrinology, then an emerging specialty. The modern era of molecular science is now offering proof-of-concept evidence to address the once intractable problem of low or absent ovarian reserve. Yet, ovarian rejuvenation by platelet-rich plasma (PRP) originates from a heritage shared with both hormone replacement therapy (HRT) and sex reassignment surgery. These therapeutic ancestors later developed into allied, but now distinct, clinical fields. Here, current iterations of intraovarian PRP are discussed with historical and cultural precursors centering on cell and tissue regenerative effects. Intraovarian PRP thus shows promise for women in menopause as an alternative to conventional HRT, and to those seeking pregnancy—either with advanced reproductive technologies or as unassisted conceptions.
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Medicines
Medicines (Basel) 2021; 8(6):29. https://doi.org/10.3390/medicines8060029
Perspective
The scientific and cultural journey to ovarian rejuvenation:
Background, barriers, and beyond the biological clock
E. Scott Sills
Plasma Research Section, FertiGen CAG/Regenerative Biology Group; San Clemente, California USA
Department of Obstetrics & Gynecology, Palomar Medical Center; Escondido, California USA
Correspondence: P.O. Box 73910 San Clemente, California 92673 USA; email: ess@prp.md
Abstract: Female age has been known to define reproductive outcome since antiquity; attempts to
improve ovarian function may be considered against a sociocultural landscape which foreshadows
current practice. Ancient writs heralded the unlikely event of an older woman conceiving as nothing
less than miraculous. Always deeply personal and sometimes dynastically pivotal, the goal to
achieve pregnancy often engaged elite healers or revered clerics for help. The sorrow of defeat be-
came a potent motif of barrenness or miscarriage lamented in art, music, and literature. Less well
known is that rejuvenation practices from the 1900’s were not confined to gynecology, as older men
also eagerly pursued methods to turn back their biological clock. This interest coalesced within the
nascent field of endocrinology, then an emerging specialty. The modern era of molecular science is
now offering proof-of-concept evidence to address the once intractable problem of low or absent
ovarian reserve. Yet, ovarian rejuvenation by platelet-rich plasma (PRP) originates from a heritage
shared with both hormone replacement therapy (HRT) and sex reassignment surgery. These thera-
peutic ancestors later developed into allied, but now distinct, clinical fields. Here, current iterations
of intraovarian PRP are discussed with historical and cultural precursors centering on cell and tissue
regenerative effects. Intraovarian PRP thus shows promise for women in menopause as an alterna-
tive to conventional HRT, and to those seeking pregnancyeither with the advanced reproductive
technologies or as unassisted conceptions.
Keywords: fertility; platelets; cytokines; angiogenesis; menopause
1. Introduction
Cellular senescence is characterized by a degenerative process accompanied by poor
tissue homeostasis and decline of organ function [1]. In clinical infertility practice, the
ovaries generally are the first to suffer age impairment over time. Traditional teaching still
embraces the basic tenet that females have a limited, non-replenishable oocyte endow-
ment present at birth, which declines during adulthood and is eventually lost at meno-
pause [2]. The basic concept of rejuvenation is not new, remaining topical yet contested.
As currently offered, ovarian rejuvenation descends from a long line of medical efforts of
varied efficacy which gained notoriety more than a century ago. In the public conscious-
ness, any discussion of rejuvenation might have gained less notice had it not been for the
developing study of gonadal physiology. Parallel improvements in surgical techniques
also made human ovary tissue grafts workable from the late 1800’s, and testicular trans-
plants for farm animals had been described even earlier [3]. Against this background, the
mystique of ‘sex gland’ modulation was ideal for showcasing via the nascent clinical field
of endocrinology.
It is now more accepted that human ovarian stem cells might persist into adulthood,
retaining a capacity to differentiate into competent oocytes under appropriate conditions
[4]. While no consensus exists regarding the exact signaling milieu necessary to elicit this
replenishment, recent work suggests that pluripotency, self-renewal, and diminished
Citation: Sills ES. The scientific and
cultural journey to ovarian rejuvena-
tion: Background, barriers, and
beyond the biological clock.
Medicines (Basel) 2021; 8(6):29.
Academic Editor: William Cho
Received: 28 April 2021
Accepted: 7 June 2021
Published: 8 June 2021
Publisher’s Note: MDPI is neutral
regarding jurisdictional claims in
published maps or affiliations.
Copyright: © 2021 by the author.
Open access publication is under
terms and conditions of the Creative
Commons Attribution license
(https://creativecommons.org/license
s/by/4.0/).
Medicines (Basel) 2021; 8(6):29. 2 of 6
follicular reserve in old age all may be subject to modulation [4,5]. This approach impacts
reproductive medicine practice and patient counseling, as older ovaries not only supply
fewer eggs but also yield cells of reduced competencychiefly due to ploidy error. More-
over, the cumulative effect of age-sensitive mutations generally accelerates the exhaustion
of ovarian reserve as reflected by diminished serum AMH and primordial follicle number
[1,5,6]. When intraovarian PRP was administered to patients not seeking pregnancy [7],
this non-pharmaceutical approach improved quality of life at least as effectively as stand-
ard hormone replacement therapy (HRT).
2. Cultural Contexts
Near the end of his life, novelist Thomas Mann (1875-1955) was among the first to
portray gynecology with accuracy in popular literature. His short story, The Black Swan,
describes a 50yr old widow yearning for recaptured youth. When menopause does re-
verse, her hopeful wish of rejuvenation seems granted. A heightened state of sexual
arousal is perceived, where vitality and libido had previously withered. But her river of
time did not really run backward. Instead, the high estrogen state was a symptom of ad-
vancing ovarian cancer. Death soon followed and the cruelty of nature’s hoax is revealed
post-mortem [8].
William Butler Yeats (1865-1939) likewise had navigated his own creative drift and
listlessness even earlier. At age 69, the Nobel laureate underwent an odd quasi-vasectomy
seeking renewal. Praising that surgery, Yeats later acknowledged his recharged energy
and sexual drive. That verve did not pass unnoticed in Dublin society, where he became
known as the ‘Gland old man’ [9]. Yeats’ literary output certainly charts an impressive
post-operative flourish of late poems, which now rank among his most acclaimed works.
Not every man enjoyed such dramatic results. Sigmund Freud (1856-1939), who at
age 67 had the same operation, obtained no impact on productivity. His quest for rejuve-
nation emerged concurrently with an awful struggle with oral cancer, entailing multiple
painful surgical revisions. It was Freud’s belief that this vasectomy-variant might assuage
his cancer, although he later admitted that ‘rejuvenation’ accomplished nothing [10].
Many less famous older men underwent this surgery in the early 20th century, in search
of both mental and physical rejuvenation.
But what surgery was done? And why exactly was it thought so worthwhile? The
concept that a type of vasectomy could yield such results traces back to the Vienna Acad-
emy and Prof. Eugen Steinach (1861-1944). What Steinach provided was a modification to
standard sterilization, a familiar operation first reported in 1899 [9]. His hemi-vasectomy,
now discredited, cut only one structure and conferred no contraceptive benefit. The belief
was that this unilateral snip would shift the work of the affected testicle away from sperm
production, and towards full-time production of male sex hormones. Steinach’s papers
were widely accepted as key contributions to the discipline of the ‘science of fatigue’ [9].
Terminology eventually trapped the teacher; gentlemen did not merely have Dr. Stein-
ach’s operation—they were ‘Steinached’ [10]. Tragically for women’s health of the day,
ovarian X-ray treatment was considered the equivalent female procedure for what Prof.
Steinach was doing for men in Vienna [10].
In 1930, Alice of Battenberg (1885-1969) a great-granddaughter of Queen Victoria,
was suffering from chronic schizophrenia and arrived at Berlin’s Tegel Castle Sanato-
rium—the world’s first psychiatric clinic. A quiet childhood in Greece was upset by the
turbulence of war and coup d'état, necessitating her family’s exile. There is no record that
she had become distraught with menopause in her mid-40s, yet the clinic director sought
the opinion of Freud who suggested ovarian X-ray therapy. This recommendation would
have aligned with accepted techniques well known to Freud himself [11]. Of course, x-
rays administered to the pelvis did nothing but increase medical problems for Princess
Alice. The harms of ionizing radiation are now better understood in the post-nuclear age,
especially cell death and endocrine collapse. Recent animal research commissioned to
Medicines (Basel) 2021; 8(6):29. 3 of 6
assess health risks for future female astronauts [12] has verified serious ovarian injury can
occur even at trace radiation doses.
Another case is the California author Gertrude Atherton (1857-1948). She penned
Black Oxen as a semi-autobiographical work, telling of an aging woman regaining youth
with ‘glandular therapy’. While operative records are missing for contemporary critique,
at age 66 Atherton did have some kind of experimental surgery and was convinced that
rejuvenation had positive results for her [10].
After his death, Prof. Steinach slipped into obscurity despite having received multi-
ple nominations for the Nobel Prize [13]. It became difficult to fit the topic of rejuvenation
in the clinical canon, yet contemporary diarists recount him as a caring professional and
dedicated researcher. Working ahead of then-accepted norms, his energies were focused
on how best to integrate findings from highly innovative animal experiments into regular
clinical practice [10]. Specifically, Steinach’s theories were among the first to posit how
reproductive capacity and sexual phenotype could be changed if given proper ‘glandular’
inducements [9]. This offered crucial support to a new physiology of chemical/steroid reg-
ulation, eclipsing the old physiology centered on nervous system regulation [13].
Little persuasion was needed to show that if rats castrated before puberty could get
back their vigor when given proper signals, then this same goal might also be possible for
humans of a certain age. In the early 20th century, the door was thus open for uncritical
belief in rejuvenation. And Steinach did not disappoint. He recorded how an innovative
therapy using substances the healthy body was already makingnot synthetic drugs or
artificial chemicalscould recharge gonadal function [10]. By 1940, it was reasonable to
expect modern science had at last unlocked the secret to rejuvenation. Along the way,
Steinach had made professional connections with experts working in other disciplines,
with rejuvenation research spinning off at least two clinical fields now well established:
hormone replacement therapy (HRT) and transgender/sex reassignment surgery. Fortu-
nately, an extensive literature exists to survey the progress in both domains.
Formal interest in HRT began in the 1960s, but reached its peak some thirty years
later. Yet, thanks to Steinach, fundamental insights were charted even earlier in the 1930s.
In 2002, clinical HRT trial data appeared on chronic postmenopausal symptoms from the
Women’s Health Initiative (WHI). The WHI found synthetic HRT had many more nega-
tive effects than expected; HRT use dropped alarmingly after subsequent publicity altered
prescribing patterns [14]. Yet HRT still dominates the pharmaceutical market with annual
valuations consistently reaching billion-dollar levels [15-18].
Experience with rejuvenation also facilitated a paradigm shift where gender identity
became reworked as a fluid target, orchestrated by sex steroids and their cyclic actions on
brain and behavior [19]. Such transitions find many unsuccessful historical antecedents,
some reaching back to ancient Rome. For example, Emperor Elagabalus (A.D. 204-222) is
alleged to have offered a substantial reward to any physician who could give him a vagina
[20], a story which secured a place for this early transgender figureeven if apocryphal.
The film The Danish Girl (based on David Ebershoff’s 1930 novel of the same name) depicts
the Dean of sex reassignment therapy, Mangus Hirschfeld (himself a contemporary of
Prof. Steinach) breaking barriers in hormone treatment. Although the protagonist, Lili
Elbe (1882-1931), was a patient and noted artist who benefited from Hirschfeld’s skill in
sex-change surgery, sadly her uterus transplant operation led to a fatal secondary sepsis.
The partnership in the 1930’s between Steinach and Hirschfeld foreshadowed what would
become transgender support [9], helping build a bridge between sex steroids and physical
identifiers. Rejuvenation research found a role for composite ‘glandular action’ in shaping
personal phenotype distinct from the accepted dogma that sex was simply a matter of
presence of ovaries or testes [19,21]. As dots were connected among HRT, behavior, and
appearance, early progress in rejuvenation produced gains in both quality of life and lon-
gevity [22]. As the published obituary for Steinach observed, ‘Not until the function of the
ductless or endocrine glands was discovered, was there any hope that old age might be
staved off’ [23].
Medicines (Basel) 2021; 8(6):29. 4 of 6
3. New Directions
The received wisdom concerning adult ovary function is being questioned, such that
the precept of inevitable oocyte decline may have exceptions. Residual quiescent ovarian
stem cells (OSCs) within aged or damaged ovaries now appear capable of differentiation
towards competent oocytes in the context of proper signaling. This hypothesis came into
sharper focus when animal research identified OSCs as population of germline precursors
not previously known. Working with adult murine ovarian tissue, such cells have been
isolated which were successfully induced to yield developmentally competent oocytes
[24]. Varied incubation and grafting techniques have been used to upregulate key meiosis-
commitment genes necessary to permit oocyte formation [25]. But what are the ‘proper
signals’ required to induce de novo egg development in adulthood? The answer seems to
involve platelet-associated cargo proteins, which are numerous and still incompletely
characterized [26]. The distinction between reported methods, where superiority or equiv-
alence has not yet been sufficiently studied, rests on ovarian injection of activated platelets
or their isolated, cell free supernatant. Such growth factors can improve tissue perfusion
via intrastromal angiogenesis, and after intraovarian injection (see Figure 1) this could be
expected to modulate oocyte competence by tempering intraovarian reactive oxygen spe-
cies and/or mRNA upregulation coordinated by PRP-associated molecular signaling [27].
In addition to numerous cytokines released by activated platelets, the releasate also in-
cludes mitochondria capable of initiating multiple physiological responses [28].
Figure 1. Injection of autologous PRP and/or condensed platelet-derived cytokines via transvaginal ultrasound
guidance (TV-USG). Meaningful improvement after this ‘ovarian rejuvenation’ is contingent on in vitro platelet
activation and release of soluble mediators to augment angiogenesis. These include epidermal growth factor,
vascular endothelial growth factor, basic fibroblast growth factor, platelet-derived growth factors, transforming
growth factor, platelet-derived angiogenesis factor, as well as several interleukins. After sample placement
within ovarian tissue, serum anti-Mullerian hormone (AMH) level is measured over three months to assess po-
tential changes in ovarian reserve. Post-treatment AMH patterns appear directly correlated with baseline plate-
let concentration [27]. Using standard IVF equipment, bilateral ovary PRP injection may be safely performed in
≤20min without anesthesia or sedation [7].
A mitochondrial transfer process also has been reported in bone marrowderived
stromal cells and mesenchymal stem cells, providing beneficial metabolic effects for re-
cipient cells [28-30]. Although this aspect of ovarian rejuvenation has (thus far) not been
the topic of research, experimental findings described by others suggest that both
 
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
Medicines (Basel) 2021; 8(6):29. 5 of 6
cytokines and mitochondria available after platelet activation are appropriate targets for
closer study.
As repair and regenerative processes organized by platelet cytokines in somatic cells
are poorly understood, their precise effects in adult human ovarian (germinal) tissue are
even less known. Yet if stem cells are indeed present in the postnatal ovary, might PRP
placed there evoke undesirable tumorigenic changes? While this might be a theoretical
risk, thus far it has not been observed in any clinical context. Because platelet cytokines
are ligands which attach to cell membrane receptorsnot the nucleustheir mechanism
of action is unlike trophic hormones [31]. Further reassurance comes from work in other
human tissue treated with PRP, where accelerated growth of healthy cells was noted with-
out triggering malignant transformation [32]. This probably explains why multiple in-
traovarian PRP methods have been used with no adverse events resulting from any tech-
nique.
Perhaps less obvious is the worry that effective ‘ovarian rejuvenation’, if utilized with
wide application, might enhance fertility so substantially as to alter world population.
This impact is unlikely, given the present condition where those countries with the highest
IVF uptake nevertheless continue to register among the lowest national birthrates. Cru-
cially, the ever-growing number of patients seeking relief from menopause will always
far exceed the infertility case sub-group, even though both populations stand to benefit
from intraovarian PRP.
Experience with autologous PRP is clearing a new non-synthetic pathway to reset the
ovarian equipoise prevalent before perimenopause. Improvement in follicular develop-
ment, hormone balance, and successful pregnancy after intraovarian PRP all have been
achieved [5,7,33,34], but the question of duration of effect is unanswered. This represents
a key limitation, but as with traditional HRT dosing [14] conditions resolved by intraovar-
ian PRP will likely also require maintenance therapy. Unfortunately, no longitudinal data
exist regarding sustained ovarian capacity improvement following PRP treatment, alt-
hough this research is planned.
4. Conclusion
While the link between platelet-derived cytokines and/or mitochondria and repro-
ductive potential awaits validation by RCTs, several case papers already offer views to
what may be clinically attainable. For example, experts in Greece [33] described a success-
ful alternative intraovarian PRP treatment leading to the first report of pregnancy in men-
opause (age 40yrs). Although the patient did not continue to delivery, the report never-
theless advances the rejuvenation field as a proof-of-concept work. In addition, embryo
genetic imbalances may benefit from upstream correction after ovarian treatment with
condensed platelet cytokines, resulting in healthy term livebirth [34]. These are promising
results and should serve as an early foundation to encourage additional research.
Funding: This research received no external funding.
Disclosure statement: The author has been issued a provisional U.S. Patent for process and treat-
ment using autologous platelet-derived cytokines for ovarian therapy.
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... But what is the basis of the proposed PRP 49 pathway to ovarian rejuvenation? 50 51 Platelets contain multiple granules which, upon activation, deliver numerous cargo 52 proteins including platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), 53 vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), transforming 54 growth factor-beta 1 (TGF-β1), insulin-like growth factor (IGF), connecting tissue growth 55 factor (CTGF), hepatocyte growth factor (HGF), and others [9,11]. The roster of releasate 56 contents seems ever growing; these moieties orchestrate cellular growth and directs repair 57 following tissue injury. ...
... Declining ovarian reserve and ineffective fertil-248 ity responses have become more formidable with advanced maternal age and cannot be 249 defeated by gonadotropins alone. Similarly, perimenopause marks a symptomatic decay 250 in female sex hormone output which at present is usually managed by exogenous hor-251 mone replacement therapy [49,50]. For both patient populations, the prospect of effective 252 'ovarian rejuvenation' would hold considerable appeal. ...
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Platelet-rich plasma (PRP) represents a physiologic signaling aggregate comprising hundreds of platelet derived cytokines obtained from blood samples, collected by standard venipuncture. As a refinement of conventional PRP, growth factors of platelet origin may be further processed to enrich this releasate after activation. Interest in PRP applications has grown over the past 15 years, and since 2016 it has attracted particular attention in experimental reproductive biology. Understandably, the claim to ‘rewind the biological clock’ has been cautiously received. It is not known how many IVF clinics now offer ‘ovarian rejuvenation’ although it is a safe assumption the number was zero prior to 2016. In contrast, considerable experience with autologous PRP (fresh and frozen) has already been reported in cardiothoracic surgery, scalp hair regrowth, dermatology, oral surgery, sports medicine and other clinical fields. While the absence of randomized placebo-controlled clinical trials regarding intraovarian PRP must be acknowledged, this deficiency did not restrain IVF or ICSI from entering mainstream fertility practice without RCT support. Nevertheless, extraordinary claims require extraordinary evidence, and this precept shapes research work here and elsewhere.
... Their study was the first to describe a novel PRP application, outlining how a non-pharmacologic method can ameliorate the consequences of ovarian senescence. While hormone replacement therapy (HRT) for menopause and advanced reproductive technologies/in vitro fertilization (IVF) for infertility are well established and familiar [2], the exploration of workable alternatives is important. Successful return of menses after menopause (as a substitute for HRT) and healthy term live births for infertility patients (either with IVF or as unassisted conceptions) following intraovarian PRP have placed this procedure under intense scrutiny, as expected. ...
... While intraovarian PRP research remains developmental and nonuniform, a related challenge exists concerning how reports discussing this experimental treatment enter the literature. Against this background, our anal-ysis addressed these open questions: (1) how have basic science research and experience with intraovarian PRP evolved in recent years, (2) what publishing options are most commonly used by those working in this specific arena, and (3) are there features of the literature that can better meet the needs of the medical authorship community? ...
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Clin Exp Reprod Med 2021 :: Objective: As clinicians and patients await consensus on intraovarian platelet-rich plasma (PRP) treatment, this project evaluated contemporary research trends in the literature. Methods: A PubMed/NLM search aggregated all ovarian PRP-related publications (n=54) to evaluate their scope, abstract utility, submission-to-publication interval, journal selected, article processing charge (APC), free reader access to full-text manuscripts, number and nationality of authors, and inclusion of international collaborators. The NIH Clinical Trials database was also audited. Results: Published output on intraovarian PRP has increased consistently since 2016, especially among investigators in Greece, Iran, USA, and Turkey. Between 2013 and 2021, 42 articles met relevancy criteria, of which 40.5% reported clinical studies, small series, or case reports, 33% described experimental animal models, and 23.8% were opinion/review papers. Only two works included a placebo control group. The submission-to-publication interval (mean±SD) was 130±96 days, there were 5.9±3.2 authors per project, and journals invoiced US $1,613±1,466 (range, $0–$3,860) for APCs. Conclusion: There was no correlation between APC and time to publish (Pearson’s r=–0.01). Abstract content was inconsistent; sample size and patient age were often missing, yet free full-text “open access” was available for most publications (59.5%). The NIH Clinical Trials portal lists eight registered studies on “ovarian rejuvenation,” of which two are actively recruiting patients, while four have been terminated or have uncertain status. Two studies have concluded, with results from one posted to the NIH website. PRP and its derivatives for ovarian treatment show early promise, but require further investigation. Research is accelerating and should be encouraged, particularly placebo-controlled RCTs.
... But what is the basis of the proposed PRP 49 pathway to ovarian rejuvenation? 50 51 Platelets contain multiple granules which, upon activation, deliver numerous cargo 52 proteins including platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), 53 vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), transforming 54 growth factor-beta 1 (TGF-β1), insulin-like growth factor (IGF), connecting tissue growth 55 factor (CTGF), hepatocyte growth factor (HGF), and others [9,11]. The roster of releasate 56 contents seems ever growing; these moieties orchestrate cellular growth and directs repair 57 following tissue injury. ...
... Declining ovarian reserve and ineffective fertil-249 ity responses have become more formidable with advanced maternal age and cannot be 250 defeated by gonadotropins alone. Similarly, perimenopause marks a symptomatic decay 251 in female sex hormone output which at present is usually managed by exogenous hor-252 mone replacement therapy [49,50]. For both patient populations, the prospect of effective 253 'ovarian rejuvenation' would hold considerable appeal. ...
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The first published description of intraovarian platelet-rich plasma (PRP) appeared in mid-2016, when a new experimental technique was successfully used in adult human ovaries to correct the reduced fertility potential accompanying advanced maternal age. Considering the potential therapeutic scope of intraovarian activated PRP and/or condensed platelet cytokines would likely cover both menopause treatment and infertility, the mainstream response has ranged from skeptical disbelief to welcome astonishment. Indeed, reports of restored menses in menopause (as an alternative to conventional hormone replacement therapy) and healthy term livebirths for infertility patients (either with IVF or as unassisted conceptions) after intraovarian PRP injection continue to draw notice. Yet any proper criticism of ovarian PRP applications will be difficult to rebut given the heterogenous patient screening, varied sample preparations, wide differences in platelet incubation and activation protocols, surgical/anesthesia techniques, and delivery methods. Notwithstanding these features, no adverse events have been reported thus far and ovarian PRP appears well tolerated by patients. Here, early research guiding the transition of ‘ovarian rejuvenation’ from experimental to clinical is outlined. Likely mechanisms are presented to explain results observed in both veterinary and human ovarian PRP research. Current and future challenges for intraovarian cytokine treatment are also discussed.
... Second, directed inhibition or promotion of protein kinases is unnecessary when the injected sample is autologous, as with PRP or its derivatives. Concerns about cancer risk from pharmacologic in vitro activation and Hippo signal disruption are valid, but experience with PRP when used in multiple tissues has never caused malignant transformation [35]. Finally, in vitro ovarian tissue culture is not a feature of any known clinical fertility PRP protocol [36]. ...
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Now I am ready to tell / how bodies are changed / into different bodies. / Descend again, be pleased / to reanimate this revival / of those marvels. / Show now exactly / how they were performed / from the beginning, / up to this moment. The Metamorphoses, Book I - Ovid (43 BC - 17)
... Ovarian perfusion corresponds with intrafollicular oxygenation, and follicles with low dissolved oxygen produce defective oocytes that are unlikely to implant when fertilized due to impaired vascularity [18,19]. Enhanced angiogenesis after PRP injections could ameliorate a locally hypoxic environment and reduce levels of intraovarian reactive oxygen species, temporarily resolving tissue dysfunction associated with hypoperfusion in the senescent ovary [20,21]. Platelet concentrates have been found to contain mitochondria capable of initiating multiple physiological responses [22]. ...
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Purpose The use of platelet-rich plasma is being investigated in reproductive medicine and clinically promoted as a fertility treatment for menopause. We aimed to review the literature on the impact of PRP on fertility in menopause. Methods A literature search was performed using the PubMed and MEDLINE search engines. The search was limited to the English language. Articles studying PRP use in menopause were selected for the purpose of this review. Results Limited case reports and case series studied fertility outcomes of PRP in menopause. Randomized controlled trials are lacking. Furthermore, no studies have been conducted to evaluate the effect of different PRP concentrations, injection techniques, or side effects on reproductive outcomes in menopausal women. Conclusion There is a dearth of data to support the routine implementation of intraovarian PRP injections for fertility restoration in menopausal women. Patients considering such therapy need to be well aware of the lack of adequate data for PRP use in menopause and should be counseled accordingly.
... Platelet cytokines interact with cell membrane-not nuclearreceptors so the biological effect is distinct from trophic hormones. 30 Experience with other tissues treated with PRP reduces doubt further, as recruitment of normal cells is achieved with no subsequent malignancy. 31 ...
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Abstract Health and life expectancy gains have pushed the overall number of menopausal patients to record levels. Because maternal age at first pregnancy also continues to rise, it is unsurprising that reduced birth rates are consistently reported across many populations. Both trends severely strain national demographics and present a socioeconomic challenge for which no satisfactory solution currently exists. Symptomatic menopause and infertility/miscarriage are met with standard therapies like hormone replacement therapy (HRT) and in vitro fertilization, respectively. Although these accepted interventions do supply some cover, both are expensive, low yield, and not without controversy. Meanwhile, ovarian steroid output and competent oocyte availability approach unrecoverable loss beyond age ~35 years, irrespective of treatment. Received wisdom holds that postnatal oogenesis in humans is impossible, a tenet which until recently encountered little serious confrontation. Reassessing this paradigm is overdue given proof‐of‐concept work on native sex steroid rejuvenation, de novo euploid oogenesis, ovulation, blastocyst development, fetal growth, and healthy term livebirths—all apparently possible with intraovarian insertion of platelet‐rich plasma (PRP). Discrete functional analysis of the full platelet‐derived cytokine array carried with PRP unfortunately for now, is incomplete. Here, selected platelet releasate constituents and measured effects are framed to address advances in wellness and women’s health. Emphasis is on cytokines best positioned to enable recovery of senescent ovarian function sufficient to suspend synthetic HRT dependency and/or permit egg retrieval and pregnancy. Whereas the chronicle of progress in other clinical fields does invite generalization of fresh platelet applications to reproductive endocrinology, basic mechanistic questions remain open.
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The inverse correlation between maternal age and pregnancy rate represents a major challenge for reproductive endocrinology. The high embryo ploidy error rate in failed in vitro fertilization (IVF) cycles reflects genetic misfires accumulated by older oocytes over time. Despite the application of different follicular recruitment protocols during IVF, gonadotropin modifications are generally futile in addressing such damage. Even when additional oocytes are retrieved, quality is frequently poor. Older oocytes with serious cytoplasmic and/or chromosomal errors are often harvested from poorly perfused follicles, and ovarian vascularity and follicular oxygenation impact embryonic chromosomal competency. Because stimulation regimens exert their effects briefly and immediately before ovulation, gonadotropins alone are an ineffective antidote to long-term hypoxic pathology. In contrast, the tissue repair properties (and particularly the angiogenic effects) of platelet-rich plasma (PRP) are well known, with applications in other clinical contexts. Injection of conventional PRP and/or its components (e.g., isolated platelet-derived growth factors as a cell-free substrate) into ovarian tissue prior to IVF has been reported to improve reproductive outcomes. Any derivative neovascularity may modulate oocyte competence by increasing cellular oxygenation and/or lowering concentrations of intraovarian reactive oxygen species. We propose a mechanism to support intrastromal angiogenesis, improved follicular perfusion, and, crucially, embryo ploidy rescue. This last effect may be explained by mRNA upregulation coordinated by PRP-associated molecular signaling, as in other tissue systems. Additionally, we outline an intraovarian injection technique for platelet-derived growth factors and present this method to help minimize reliance on donor oocytes and conventional hormone replacement therapy.
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One explanation for why downstream gonadotropin protocol changes during IVF commonly arrive too late to have significant effects is that embryo development actually begins during oogenesis. Thus, efforts to modify the chromosomal status of blastocysts must address the ovarian milieu well in advance of follicular recruitment. A 42 year old woman with primary infertility of 3 year duration attended with her partner. Five previous IVF cycles had produced 20 embryos, but all had genetic abnormalities and no embryo transfer was performed. Karyotypes and all lab tests were normal for both partners. 3 months before her IVF here, she received isolated platelet-derived growth factors injected into both ovaries as a cell-free, enriched substrate. Genetic assessments were via whole genome amplification and DNA tagmentation and PCR adapter sequences. Comprehensive chromosomal screening was carried out by dual-indexed sequencing of pooled libraries on the MiSeq™ platform. From this IVF cycle one euploid 46, XY blastocyst was produced and vitrified on the day of trophectoderm biopsy. 9 days after frozen embryo transfer, serum human chorionic gonadotropin was 250 mIU/ml and a transvaginal ultrasound at 6 week gestation confirmed a single intrauterine pregnancy with fetal heart at 153/min. A healthy male infant was delivered by c-section at 39 weeks' gestation. While cellular and molecular events directing the oocyte-to-embryo transition are incompletely characterized, processes related to ovarian stem cell differentiation, mitochondrial dynamics, and mRNA storage, translation, and degradation likely are relevant. It appears that intraovarian application of autologous platelet-derived growth factors, when used before IVF, can impact oocyte integrity and facilitate euploid blastocyst development. Although research on intraovarian injection of autologous activated platelet rich plasma has already shown improved quantitative IVF responses, this is the first description of qualitative improvements in embryo genetics after intraovarian injection of autologous platelet-derived growth factors.
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The history of hormone replacement therapy (HRT) started in the 1960s, with very high popularity in the 1990s. The first clinical trials on HRT and chronic postmenopausal conditions were started in the USA in the late 1990s. After the announcement of the first results of the Women’s Health Initiative (WHI) in 2002, which showed that HRT had more detrimental than beneficial effects, HRT use dropped. The negative results of the study received wide publicity, creating panic among some users and new guidance for doctors on prescribing HRT. The clear message from the media was that HRT had more risks than benefits for all women. In the following years, a reanalysis of the WHI trial was performed, and new studies showed that the use of HRT in younger women or in early postmenopausal women had a beneficial effect on the cardiovascular system, reducing coronary disease and all-cause mortality. Notwithstanding this, the public opinion on HRT has not changed yet, leading to important negative consequences for women’s health and quality of life.
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In clinical infertility practice, one intractable problem is low (or absent) ovarian reserve which in turn reflects the natural oocyte depletion associated with advancing maternal age. The number of available eggs has been generally thought to be finite and strictly limited, an entrenched and largely unchallenged tenet dating back more than 50 years. In the past decade, it has been suggested that renewable ovarian germline stem cells (GSCs) exist in adults, and that such cells may be utilized as an oocyte source for women seeking to extend fertility. Currently, the issue of whether mammalian females possess such a population of renewable GSCs remains unsettled. The topic is complex and even agreement on a definitive approach to verify the process of ‘ovarian rescue’ or ‘re-potentiation’ has been elusive. Similarities have been noted between wound healing and ovarian tissue repair following capsule rupture at ovulation. In addition, molecular signaling events which might be necessary to reverse the effects of reproductive ageing seem congruent with changes occurring in tissue injury responses elsewhere. Recently, clinical experience with such a technique based on autologous activated platelet-rich plasma (PRP) treatment of the adult human ovary has been reported. This review summarizes the present state of understanding of the interaction of platelet-derived growth factors with adult ovarian tissue, and the outcome of human reproductive potential following PRP treatment.
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Background: Gender dysphoria is described as a mismatch between an individual's experienced or expressed gender and their assigned gender, based on primary or secondary sexual characteristics. Gender dysphoria can be associated with clinically significant psychological distress and may result in a desire to change sexual characteristics. The process of adapting a person's sexual characteristics to their desired sex is called 'transition.' Current guidelines suggest hormonal and, if needed, surgical intervention to aid transition in transgender women, i.e. persons who aim to transition from male to female. In adults, hormone therapy aims to reverse the body's male attributes and to support the development of female attributes. It usually includes estradiol, antiandrogens, or a combination of both. Many individuals first receive hormone therapy alone, without surgical interventions. However, this is not always sufficient to change such attributes as facial bone structure, breasts, and genitalia, as desired. For these transgender women, surgery may then be used to support transition. Objectives: We aimed to assess the efficacy and safety of hormone therapy with antiandrogens, estradiol, or both, compared to each other or placebo, in transgender women in transition. Search methods: We searched MEDLINE, the Cochrane Central Register of Controlled Trials (CENTRAL), Embase, Biosis Preview, PsycINFO, and PSYNDEX. We carried out our final searches on 19 December 2019. Selection criteria: We aimed to include randomised controlled trials (RCTs), quasi-RCTs, and cohort studies that enrolled transgender women, age 16 years and over, in transition from male to female. Eligible studies investigated antiandrogen and estradiol hormone therapies alone or in combination, in comparison to another form of the active intervention, or placebo control. Data collection and analysis: We used standard methodological procedures expected by Cochrane to establish study eligibility. Main results: Our database searches identified 1057 references, and after removing duplicates we screened 787 of these. We checked 13 studies for eligibility at the full text screening stage. We excluded 12 studies and identified one as an ongoing study. We did not identify any completed studies that met our inclusion criteria. The single ongoing study is an RCT conducted in Thailand, comparing estradiol valerate plus cyproterone treatment with estradiol valerate plus spironolactone treatment. The primary outcome will be testosterone level at three month follow-up. Authors' conclusions: We found insufficient evidence to determine the efficacy or safety of hormonal treatment approaches for transgender women in transition. This lack of studies shows a gap between current clinical practice and clinical research. Robust RCTs and controlled cohort studies are needed to assess the benefits and harms of hormone therapy (used alone or in combination) for transgender women in transition. Studies should specifically focus on short-, medium-, and long-term adverse effects, quality of life, and participant satisfaction with the change in male to female body characteristics of antiandrogen and estradiol therapy alone, and in combination. They should also focus on the relative effects of these hormones when administered orally, transdermally, and intramuscularly. We will include non-controlled cohort studies in the next iteration of this review, as our review has shown that such studies provide the highest quality evidence currently available in the field. We will take into account methodological limitations when doing so.
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The trend in our society to delay procreation increases the difficulty to conceive spontaneously. Thus, there is a growing need to use assisted reproduction technologies (ART) to form a family. With advanced maternal age, ovaries not only produce a lower number of oocytes after ovarian stimulation but also a lower quality-mainly aneuploidies-requiring further complex analysis to avoid complications during implantation and pregnancy. Although there are different options to have a child at advanced maternal age (like donor eggs), this is not the preferred choice for most patients. Unless women had cryopreserved their eggs at a younger age, reproductive medicine should try to optimize their opportunities to become pregnant with their own oocytes, when chances of success are reasonable. Aging has many causes, but telomere attrition is ultimately one of the main pathways involved in this process. Several reports link telomere biology and reproduction, but the molecular reasons for the rapid loss of ovarian function at middle age are still elusive. This review will focus on the knowledge acquired during the last years about ovarian aging and disease, both in mouse models of reproductive senescence and in humans with ovarian failure, and the implication of telomeres in this process. In addition, the review will discuss recent results on ovarian rejuvenation, achieved with stem cell therapies that are currently under study, or ovarian reactivation by tissue fragmentation and the attempts to generate oocytes in vitro.
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During the winter of 1930, Princess Alice of Battenberg was admitted to Kurhaus Schloß Tegel, where she was diagnosed with schizophrenic paranoia. When Freud was consulted about her case by Ernst Simmel, the Sanatorium’s Director, he recommended that the patient’s ovaries be exposed to high-intensity X-rays. Freud’s suggestion was not based on any psychoanalytic treatment principles, but rooted in a rejuvenation technique to which Freud himself had subscribed. In recommending that psychotic patients should be treated with physical interventions, Freud confirmed his conviction that the clinical applicability of psychoanalysis should not be extrapolated beyond the neuroses, yet he also asserted that a proper consideration of endocrinological factors in the aetiology and treatment of the psychoses should never be excluded.
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Rational: Extracellular vesicles, including microvesicles (MVs), are increasingly recognized as important mediators in cardiovascular disease. The cargo and surface proteins they carry are considered to define their biological activity, including their inflammatory properties. Monocyte to endothelial cell signaling is a prerequisite for the propagation of inflammatory responses. However, the contribution of MVs in this process is poorly understood. Objective: To elucidate the mechanisms by which MVs derived from activated monocytic cells exert inflammatory effects on endothelial cells. Methods and Results: LPS-stimulated monocytic cells release free mitochondria and MVs with mitochondrial content as demonstrated by flow cytometry, quantitative PCR, Western Blot and transmission electron microscopy. Using RNAseq analysis and qRT-PCR we demonstrated that both mitochondria directly isolated from and MVs released by LPS-activated monocytic cells, as well as circulating MVs isolated from volunteers receiving low-dose LPS-injections, induce type I Interferon and TNF responses in endothelial cells. Depletion of free mitochondria significantly reduced the ability of these MVs to induce type I Interferon and TNF-dependent genes. We identified mitochondria-associated TNF and RNA from stressed mitochondria as major inducers of these two responses. Finally, we demonstrated that the proinflammatory potential of MVs and directly isolated mitochondria was drastically reduced when they were derived from monocytic cells with non-respiring mitochondria or monocytic cells cultured in the presence of pyruvate or the mitochondrial ROS scavenger MitoTEMPO. Conclusions: Mitochondria and mitochondria embedded in MVs constitute a major subset of extracellular vesicles released by activated monocytes and their proinflammatory activity on endothelial cells is determined by the activation status of their parental cells. Thus, mitochondria may represent critical intercellular mediators in cardiovascular disease and other inflammatory settings associated with type I IFN and TNF signaling.