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Accepted Manuscript
Natural hormone replacement therapy with a functioning ovary afterthe menopause: dream or reality?
Jacques Donnez , Marie-Madeleine Dolmans
PII: S1472-6483(18)30325-0DOI: 10.1016/j.rbmo.2018.05.018Reference: RBMO 1963
To appear in: The End-to-end Journal
Received date: 31 January 2018Revised date: 28 May 2018Accepted date: 29 May 2018
Please cite this article as: Jacques Donnez , Marie-Madeleine Dolmans , Natural hormone replace-ment therapy with a functioning ovary after the menopause: dream or reality?, The End-to-end Journal(2018), doi: 10.1016/j.rbmo.2018.05.018
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Short title: Natural hormone replacement therapy
Natural hormone replacement therapy with a functioning ovary after the menopause:
dream or reality?
Jacques Donnez,a Marie-Madeleine Dolmans,
b, c
aSociété de Recherche pour l'Infertilité, Avenue Grandchamp 143, 1150 Brussels, Belgium
Brussels, Belgium
bPôle de Gynécologie, Institut de Recherche Expérimentale et Clinique (IREC), Université
Catholique de Louvain, Brussels, Belgium
cGynecology Department, Cliniques Universitaires Saint Luc, Avenue Hippocrate 10, 1200
Brussels, Belgium
Corresponding author.
E-mail address: [email protected] (J. Donnez).
Key message
Cryopreservation of ovarian tissue at a young age followed by reimplantation may restore
long-term ovarian endocrine function that can persist for more than 7 years (even more if the
procedure is repeated) and prevent menopause-related conditions.
Abstract
At the dawn of humanity, it was rare to live beyond the age of 35 years, so the ovary was
intended to function for a woman’s entire life. Nowadays, it is not unusual for women to live
into their 80s. This means that many of them spend 30–40% of their lives in the menopause at
increased risk of various conditions associated with an absence of oestrogens (cardiovascular
disease, bone mineral density loss). Reimplantation of frozen–thawed ovarian tissue is able to
restore long-term ovarian endocrine function that can persist for more than 7 years (12 years if
the procedure is repeated). If ovarian tissue reimplantation is capable of restoring ovarian
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activity after menopause induced by chemotherapy, radiotherapy, surgery, or a combination
of all three, why not propose it to recover sex steroid secretion after natural menopause and
prevent menopause-related conditions in the ageing population? In this application, the graft
site could be outside the pelvic cavity, e.g., forearm or rectus muscle. Could ovarian tissue
freezing at a young age followed by reimplantation upon reaching menopause be the anti-
ageing therapy of the future? Sufficient existing evidence now surely merits serious debate.
KEYWORDS: hormone replacement therapy, ovary, ovarian tissue reimplantation,
menopause
<A>The ovary from birth to menopause
During fetal life, 100–2000 primordial germ cells enter a massive proliferation process. By
mid-gestation, there are several million potential oocytes, but 85% of them are lost before
birth. After birth, the number of primordial follicles, also known as non-growing follicles,
decreases year on year until puberty, even in the absence of ovarian activity (Wallace and
Kelsey, 2012) (Figure 1).
Of around 1 million oocytes per ovary at birth, only 450 are actually used. Indeed, the decline
in follicle numbers continues throughout reproductive life, during which time about 450
monthly ovulatory cycles occur, with most follicles undergoing atresia (degeneration and
resorption) during their growth phase. Cyclic folliculogenesis and ovulation, associated with
massive follicular atresia and ageing-induced apoptosis, result in ovarian atrophy and reduced
fertility (Wallace and Kelsey, 2012; Donnez and Dolmans, 2013).
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Among numerous mechanisms proposed to explain decreased fertility in women aged over 40
years, poor oocyte quality, characterized by abnormalities in the meiotic spindle, chromosome
misalignment and shortened telomeres, is the most frequently cited (Liu and Keefe, 2002; Liu
and Li, 2010; Donnez and Dolmans, 2013). Depletion of the ovarian reserve at a young age
may also be the consequence of medical treatment, such as chemotherapy with or without
radiotherapy (Donnez and Dolmans, 2013; 2017a).
Ovarian surgery for severe and recurrent endometriosis or recurrent ovarian cysts is another
common cause of ovarian reserve decline, as are known risk factors for premature menopause
(Turner syndrome, family history) (Donnez et al., 2012; Donnez and Dolmans, 2013; 2017a).
At menopause, follicular density is low. About 1500 primordial follicles remain, but most are
inactive (Wallace and Kelsey 2012). According to Amundsen and Diers (1970) and Lobo et
al. (2013), the age of menopause has changed very little over the centuries, whereas life
expectancy has increased (Amundsen and Diers, 1970; 1973; Lobo, 2013).
<A>The facts
When humans first walked this earth, life expectancy rarely exceeded 35 years and the ovary
was intended to go on working for an entire lifetime. These days, it is not unusual to live
beyond 80 years, begging the question: is it possible for natural ovaries, each containing
several million oocytes at mid-gestation, to continue functioning until death?
A better way of life and improved health care were able to boost life expectancy in the space
of only 1 century, from 48.3 years in 1900 to 80 years in 2000, essentially thanks to advances
in public health measures and efforts. In the 20th century, despite a brief dip caused by the
1918 flu pandemic (Figure 2) (Smith and Bradshaw, 2006), the average lifespan increased by
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more than 30 years (in the USA and the Western world). It is estimated that 50% of all girls
born today will live to over 100 years of age in many countries. The consequence of this
extended longevity is that many women will spend even greater proportions of their lives in
the menopause, exposed to an elevated risk of diseases linked to the absence of oestrogens,
such as cardiovascular disease and bone mineral density loss (Lobo, 2013; 2017).
<A>Does hormone replacement therapy alleviate menopausal symptoms?
In the 1980s, several studies (including meta-analyses) suggested that hormone replacement
therapy (HRT) could be beneficial for preventing osteoporosis, coronary heart disease and
dementia, leading to decreased mortality. In 1992, the American College of Physicians
recommended HRT for preventing coronary disease (American College of Physicians, 1992).
In the early 2000s, however several randomized trials (Women’s Health Initiative [WHI]
[Rossouw et al., 2002], Million Women Study, Lancet, 2003) suggested that the risks,
including for breast cancer, outweighed any benefits. This unfortunately led to new
recommendations being made, resulting in a 50% drop in HRT use (Lobo, 2013). For this
reason, in 2013, Lobo asked a crucial question: ‘Where are we, 10 years after the WHI?’ He
used age stratification, reanalysed data from the original randomized trials, along with more
recent studies, and found that women aged 50–59-years or within 10 years of menopause
taking HRT had lower rates of coronary heart disease and all-cause mortality, and not did
show any increase in perceived risks, including for breast cancer compared with women
taking HRT (Lobo, 2013; 2016; 2017; Lobo et al. 2016).
When cumulative data from the group aged 50–59 years taking part in the conjugated equine
oestrogens alone trial of the WHI were analysed after 13 years, the relative risk for coronary
heart disease was 0.65 (0.44 to 0.96), for breast cancer 0.76 (0.52 to 1.11) and for total
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mortality 0.78 (0.59 to 1.03) (Lobo et al. 2016; Lobo, 2017). Hormone replacement therapy is
also known to decrease the incidence of menopausal symptoms and risk of osteoporotic
fractures, improving quality of life.
Hence, the risk–benefit balance is positive for HRT use, with risks considered rare in healthy
women aged 50–60 years, something known as the ‘timing hypothesis’ (Lobo, 2016; 2017).
As suggested by Lobo et al. (2016) (Figure 3), having already come full circle with HRT
since its introduction, we should now be looking at using it in the context of a general
prevention strategy for women approaching menopause.
<A>Ovarian tissue reimplantation as potential HRT
Only two studies have reported data on ovarian tissue reimplantation as potential HRT. The
first, by Callejo et al. (2001), described a series of three patients undergoing hysterectomy
and bilateral oophorectomy, followed by immediate reimplantation of ovarian cortical tissue
in the abdominal wall. Ovarian secretion was observed 4–5 months after surgery in two of the
three cases, but only for a ‘short reproductive span’. The authors concluded that it is unlikely
that heterotopic grafts would have the longevity to be an adequate substitute for HRT after
normal menopause. Clearly, their conclusion cannot be generalized, as the women involved
were aged 45–49 years and their ovarian reserve was already extremely depleted.
The second study, by Kiran et al. (2005), is a case report. A 44-year-old woman operated on
for uterine fibroids received an ovarian tissue graft (10 cortical strips) implanted in the
Pfannenstiel incision site above the rectus abdominis fascia. Folliculogenesis was still evident
by ultrasonography 18 months later, as were low LH and FSH levels, despite having shown
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an increase at 12 and 15 months of follow-up. No further details on this case have been
reported.
<A>Duration of ovarian activity after reimplantation of frozen ovarian tissue in case of
‘iatrogenic’ menopause
<B>Donnez and Dolmans
In our series, we observed restoration of ovarian activity with resumption of menses in 100%
of cases when primordial follicles were present in frozen biopsies (Donnez and Dolmans,
2015b). In an earlier series, ovarian activity failed to resume in three patients with no follicles
in their grafted tissue (Donnez and Dolmans, 2013; 2015a), highlighting the importance of an
intact follicular reserve.
The long-term duration of ovarian function in a series of five women who underwent ovarian
tissue cryopreservation before the age of 22 years (median 19 years), and reimplantation some
years, later is shown in Figure 4. Ovarian activity was restored for a period of 6–7 years. By
repeating the procedure, this can be extended to over 12 years (Donnez and Dolmans, 2015b)
(Figure 4).
The ovaries of a newborn girl contain an average of 1 million primordial follicles, dropping to
100,000 at 20 years of age and 65,000 at 25 years (95% prediction interval 7700–546,000),
according to Wallace and Kelsey (2010). Ideally, ovarian biopsies should be taken when
follicular density is high (between the ages of 20 and 25 years) because, as demonstrated by
our team, ovarian function can then be restored for long periods of time (Donnez and
Dolmans, 2015b).
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<B>Andersen and Kristensen
In a recent paper, Andersen and Kristensen (2015) reported that four patients underwent their
first tissue transplantation procedure more than 10 years ago in their centre. Two of them
experienced ovarian activity for 6–7 years, similar to results obtained in our series. The other
two underwent a second transplantation and still have functioning ovaries 11 years after the
initial procedure.
<B>Kim
In a study by Kim (2012), four patients aged between 27 and 37 years had their ovarian tissue
cryopreserved between 1999 and 2004. Reimplantation was carried out between 2001 and
2011. Ovarian tissue slices were grafted to a heterotopic site (between the rectus muscle and
rectus sheath) and long-term follow-up was initiated (Kim, 2012). Recovery of ovarian
function was achieved but was relatively short (3–6 months). The patients underwent a second
transplantation. In one woman, low FSH and high oestradiol levels proved that the graft was
still functioning after 7 years. This clearly shows that, if the goal is restoring ovarian function
but not fertility, a heterotopic location (forearm, abdominal wall) could be an easy and
effective site for reimplantation (Kim, 2014).
According to Kim (2012; 2014), the heterotopic graft produced progesterone secretion.
A recent paper (Damásio et al., 2016) reported that heterotopic transplantation was able to
preserve ovarian follicle integrity in an animal model, but the manuscript failed to report
endocrine secretion. In a study by Suzuki et al. (2012), it was reported that heterotopic
autografts can give rise to long-term ovarian function, with progesterone values over 10
mg/ml during the luteal phase. Progesterone secretion was also documented in another animal
model (Lee et al., 2017) after autografting of vitrified ovarian tissue to a heterotopic site.
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<A>Could removal of biopsies or ovaries cause any harm?
Removal of five to six biopsies of 1 cm in length and 5 mm in width will have little if any
effect on fertility or age of menopause. Even removal of a whole ovary is known to have a
negligible effect. Indeed, it is now well proven that women with one ovary remain as fertile as
women with both (Lass et al., 1997; Blanco et al., 2001). Two studies (Yasui et al., 2012;
Bjelland et al. 2014) have also shown that onset of menopause is only marginally affected in
women with only one ovary, who tend to start their menopause around 1 year earlier. We
may, therefore, state with some degree of certainty that removal of less than 30% of one ovary
has a minimal effect on the ovarian reserve and subsequent follicular recruitment (Donnez and
Dolmans, 2017a).
<A>The future
In 2015, two different teams (Andersen and Kristensen, 2015; Donnez and Dolmans 2015b)
demonstrated that long-term endocrine function could persist for more than 7 years (12 years
with a repeat procedure) after frozen–thawed ovarian tissue reimplantation (Figure 4). They
suggested that restoration of endocrine function could prevent menopause-related conditions,
such as osteoporosis and other complaints in an ageing population.
Therefore, having established that ovarian tissue reimplantation is able to restore ovarian
activity after induced menopause, why not propose it to restore sex steroid secretion after
natural menopause? In this instance, the graft site could be heterotopic, namely outside the
pelvic cavity, e.g. the forearm, rectus muscle, as the goal here is not fertility restoration
(Figure 5). This makes the procedure less invasive, potentially achievable under local
anaesthesia, and feasible even if severe pelvic adhesions are present (Table 1). As suggested
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by Andersen and Kristensen (2015), this approach should initially be considered in women
with ovarian tissue already frozen. Undoubtedly, this application will become increasingly
widespread in the future (Donnez and Dolmans, 2017).
When the implants stop functioning, surgery may be repeated and endocrine function restored
for longer. Owing to improvements in new techniques favourably affecting the time needed
for revascularization, follicle loss rates may be reduced and the benefits of grafting might be
seen sooner and for longer periods (Manavella et al., 2017).
Questions surrounding possible risks and uncertainties will, of course, be raised and must be
satisfactorily addressed (Andersen and Kristensen, 2015; Donnez and Dolmans, 2015b), but
some remain unanswered at present. Is the endometrium adequately protected by progesterone
secretion? Is progesterone secreted by ovarian tissue grafted to a heterotopic site? Kim (2012;
2014) has the most extensive experience in heterotopic grafting and has confirmed that
progesterone secretion was similar to that observed in the case of orthotopic grafting.
Moreover, a progesterone level of 5 mg/ml for 10 days is enough to induce differentiation to
the endometrial secretory phase, and this level is easily achieved even after heterotopic
grafting. Heterotopic transplantation is not optimal for oocyte quality, but corpora lutea may
develop in heterotopic sites. Stern et al. (2013; 2014) reported that heterotopic grafts, while
not optimal, nevertheless allow the potential for pregnancy and live birth. Other authors
(Rosendahl et al., 2006; Demeestere et al., 2009) have also demonstrated ovarian activity and
progesterone secretion after heterografting of human ovarian tissue. Other issues, however,
are an even greater cause of concern and need to be thoroughly investigated.
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Is there an increased risk of cancer after tissue reimplantation? Although we are unable to
offer any conclusive response at this stage, the debate should at least be opened, taking into
account the well-balanced benefits of HRT. Would postponing the age of menopause increase
the risk of breast cancer? The question is appropriate, but the risks attributed to HRT have
been overestimated (Sitruk-Ware, 2007). According to a recent paper by Lobo (2017), the
risk–benefit balance of HRT use in healthy young women aged 50–59 years or within 10
years of menopause shows lower rates of all-cause mortality, without any increase in breast
cancer. Moreover, although HRT should be primarily oestrogen-based, no particular HRT
regimen has emerged as the frontrunner (Lobo, 2017).
Ovarian neoplasms originating from ovarian tissue grafted beneath the skin are the subject of
the most heated debate related to the procedure. It should be stressed, however, that follow-up
of implants placed under the skin is straightforward (Table 1), and resection is possible if
implants require excision.
When evaluating the cancer risk of grafted tissue, it is logical to compare values with those of
a normal intra-abdominal ovary. Furthermore, if the biopsy was taken at the age of 20–25
years, the risk of developing ovarian cancer over a 10-year period is low. Indeed, this risk
increases essentially after the natural menopause, when the ovary is more than 50 years old.
An alternative way of avoiding the threat of ovarian cancer involves isolating follicles,
transferring them inside a specially created scaffold (artificial ovary), and then reimplanting
this scaffold in the forearm or abdominal wall (Figure 5).
In conclusion, if ovarian tissue freezing and reimplantation can restore ovarian hormone
function in case of iatrogenic menopause, why not consider it for naturally occurring
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menopause (Donnez and Dolmans, 2017)? In response to the opinion paper by Andersen and
Kristensen (2015a), Von Wolff et al. (2015) ask the question: ‘is it really more advantageous
for women’s health than menopausal hormone replacement therapy?’ They argue that women
without a uterus should be given conventional oestrogen therapy, whereas transplantation of
frozen–thawed ovarian tissue may be beneficial to patients with an intact uterus, as there is a
need for progesterone. They also claim that no studies support grafting of ovarian tissue as a
way of postponing menopause.
In their subsequent response, Andersen and Kristensen (2015b) emphasize their central
message, maintaining that individualization is key and that new diagnostic tools should be
considered when choosing the type of HRT and avoiding menopausal effects. Strong familial
predisposition to osteoporosis, previous hysterectomy, age at menopause and many other
factors need to be considered in such individualized therapy.
Clinical trials to investigate this approach are clearly needed, but we should bear in mind that
most natural oestrogens are produced by the ovary itself, and not by a pharmaceutical
company (Donnez and Dolmans, 2017b).
In another letter to the editor, Patrizio and Caplan (2015) concluded that both medical and
ethical issues must be fully addressed before this alternative can be offered as potential
menopause treatment. They stressed the key moral challenge regarding efficacy, questioning
the capacity of ovarian tissue harvested at a young age to maintain its own ‘youth’ and not
adapt to the actual age of the patient, ceasing to function much earlier than anticipated. We
may quell such misgivings, having proved that ovarian function can be maintained for 6–7
years or more, and that the procedure, being easily repeatable (at least once), can extend
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ovarian function for over 12 years (Andersen and Kristensen 2015a; 2015b; Donnez and
Dolmans, 2015b).
We acknowledge that numerous issues must still be satisfactorily resolved, and that animal
research and human investigations should be conducted according to morally responsible
standards. Nevertheless, we need to establish whether ovarian tissue freezing at a young age
followed by reimplantation at menopause could indeed be the anti-ageing therapy of the
future. We believe we now have enough evidence to initiate a meaningful debate on this
subject.
Acknowledgements
The authors thank Guillaume E Courtoy for his input to the figures. They also thank Mira
Hryniuk, BA, for reviewing the English language of the manuscript and Deborah Godefroidt
for her administrative help.
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Table 1 – Advantages of heterotopic transplantation to restore ovarian function.
Advantages
Less invasive procedure
Repeat transplantations possible
Feasible even with severe pelvic adhesions
Preferred method for restoration of ovarian
function (not fertility)
Allows close monitoring for potential
recurrence of malignancy in grafts
Figure legend
Figure 1 – The ovarian reserve throughout a woman’s life, from conception to age 55 years.
Only around 1000 follicles remain at menopause. Adapted from Wallace WH and Kelsey
TW. PLOS ONE 27, e8772, 2010; published under an open-access license by PLoS. Donnez J
and Dolmans MM propose ovarian tissue reimplantation when women reach the menopause.
Ideally, their tissue should have been removed and frozen at the age of 20–25 years. Adapted
from Wallace and Keysey, PLOS ONE, 2010.
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Figure 2 – Life expectancy in the US (based on National Vital Statistics Reports [Volume 58,
Number 21] and Smith and Bradshaw, 2006). Adapted from National Vital Statistics Reports
Volume 58, number 21, and Smith and Bradshaw, Demography, 2006.
Figure 3 – Lobo’s full circle (Lobo, Nature Reviews Endocrinology, 2017), giving rise to the
timing hypothesis. Adapted from Lobo, Nature Reviews Endocrinology, 2017. HRT, hormone
replacement therapy; MWS, Million Women Study; WHI, Women’s Health Initiative.
Figure 4 – Long-term duration of ovarian function after orthotopic transplantation in a series
of five women who had their ovarian tissue cryopreserved aged younger than 22 years.
Adapted from Donnez and Dolmans, Journal of Assisted Reproduction and Genetics, 2015,
and New England Journal of Medicine, 2017.
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Figure 5 – Ovarian tissue freezing followed by reimplantation upon reaching menopause.
Ovarian tissue may be grafted to a heterotopic site in the form of ovarian tissue strips, or
inside an artificial ovary containing isolated primordial follicles (Based on Donnez and
Dolmans, New England Journal of Medicine, 2017). Adapted from Donnez and Dolmans,
New England Journal of Medicine, 2017.
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Declaration
JD has been a member of the Scientific Advisory Board (SAB) of PregLem SA since 2007.
He receives grants and fees for lectures and coverage of travel expenses to investigator
meetings of PEARL studies from the Gedeon Richter Group. He was the principal
investigator of the four PEARL trials. MMD has no conflict of interest in relation to the
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paper. Her salary is partially (50%) paid by the Fonds National de la Recherche Scientifique
de Belgique-FNRS (grant number 5/4/150/5).
Author biography
Jacques Donnez was appointed Professor Emeritus at the Catholic University of Louvain in
2012. He has published over 600 original articles in peer-review journals. He was the first
President of the International Society for Fertility Preservation (to end 2010) and was elected
to the Royal Belgian Academy of Medicine in 2009.