What may be causes of DOR
at an early age of 30-35 yrs?? The causes of causes of POF/DOR
/ POI
“Premature ovarian
Insufficiency’ ?? Ans:-1) Iatrogenic 2) Autoimmune 3) Genetic including familial genetic causes 5) chromosomal abnormalities like
X Chromosome abnormalities
6) Viral infections 7) ovarian surgery /malignancy.,
What is
the Clinical Presentations like?
Think of heading DOR/POF when anyone is present in early
thirties:-- if there is a) sudden Oligomeno/
b) unexplained subfertility c) Poor
response to high dose of stimulation d) Low AFC
or & low AMH (Antimullerian hormone) . Caution :: Are U dealing with
a case of unexplained subfertility in age of F partner
has just crossed 30 yrs?? !!! Many cases
of unexplained subfertility are in fact impending POF(Dwindling ovarian function)
Oligomeno/ subfertility/ Women with premature ovarian insufficiency may present
with oligo or amenorrhoea in association with climacteric symptoms, hot flushes
or night sweats. Sometimes these symptoms first become apparent when a woman
discontinues the oral contraception pill in order to try for a pregnancy. In
many cases, the diagnosis is made by the fertility specialist, when
investigating a woman with infertility but normal menstrual cycles. The blood
test may reveal an elevated FSH, reduced oestradiol or an abnormally low AMH.
Indeed, it is likely that many cases of unexplained infertility are in fact due
to undiagnosed premature ovarian failure.
The symptoms of premature
ovarian infertility include irregular periods, amenorrhoea and the typical
menopausal symptoms.
In the long term, women
with premature ovarian insufficiency are also at risk of osteoporosis, heart
disease and there is also an associated increase in overall mortality . The
most distressing symptom of premature ovarian failure is often loss of
fertility with 54 % of women reporting this as the most distressing consequence
of their diagnosis.
It is thought that around
5 % of women with this diagnosis will go on to conceive but this is variable, a
younger woman with a diagnosis is more likely to conceive than a woman in her
late 30s with the same diagnosis. There is no effective intervention to enhance
the likelihood of spontaneous or natural conception. One study has shown that
26 % of women with premature ovarian insufficiency experienced intermittent
ovarian function and few( 5 %) went on to conceive.
What may be the optimum
time after which Ovum donation Shoud be strongly considered??
Ans:-The vast majority of those who conceived did so in the first year
indicating that the longer the period of amenorrhoea, the less likely it is
that a woman will conceive naturally. Women who present with premature ovarian
failure and primary amenorrhoea are
.2 Symptoms and long term
consequences of premature ovarian insufficiency
also very unlikely to
conceive as compared to those who present with secondary amenorrhoea.
The average age at which
women give birth has been rising in the recent decades and in the UK the
average age of a woman having giving birth is 29.7 years with nearly half of
women being over the age of 30 (Fig. 11.1). The average age of first birth is
currently 27.9 compared to 26.6 in 2001 (Office for national statistics 2013).
An increasing number of women who have delayed having children will therefore
not be able to do so due premature ovarian insufficiency occurring in the third
or fourth decade of life.
Most women are aware of
the biological advantages in having children earlier but are prevented from
doing so because of complex economic, educational and social factors.
Many women, therefore,
wish to be reassured or at least want to know the state of their ovarian
function and how much longer they have before their fertility is significantly
reduced. The clinical history, assessment of ovarian reserve and response to
ovarian stimulation may be used for this.
The clinical predictions
tend not to be very helpful as there may already be some degree of decline of
ovarian function before this is suspected clinically as when a woman presents
with a history of Oligomenorrhoea associated climacteric symptoms. A history of
autoimmune disease, particularly Addison’s and autoimmune thyroiditis may also
increase the likelihood that a woman will develop premature ovarian failure.
Family history can
sometimes be helpful particularly if the mother or any older sisters had an
early menopause.
A recent study from
Denmark revealed that women whose parents had an early menopause were more
likely to have reduced AMH and antral follicle count.
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Interestingly, there was no significant association with elevated FSH, serum oestradiol or ovarian volume [3].
Ovarian reserve can be
defined as the size of the ovarian follicle pool as associated with the quality
with the oocytes. These naturally decline with age resulting in reduced
fertility. Fertility specialists employ a number of methods to assess ovarian
reserve as a way of predicting outcome to treatment, in particular in
predicting response to ovarian stimulation and therefore helping decide on the
appropriate dose of FSH to be used for stimulation. Assessment of ovarian
reserve is typically carried out in the early follicular phase FSH. An elevated
FSH indicating some degree of ovarian failure. Antral follicle count has also
been used, however, its reliability is very much operator dependent. Recently,
AMH has been used and appears to be more reliable than FSH or AFC. A further
advantage is that AMH can be carried out at any time during the cycle; however,
while ovarian reserve tests are useful in predicting response to ovarian
stimulation, they cannot predict menopause because follicular atresia does not
occur as a constant and uniform rate. It has been suggested that the rate of
decline in AMH rather than absolute AMH levels may be useful in predicting the
age of the menopause .However, this is of limited clinical value as the average
age of women in this study was 41 and the shortest time interval required was
3.5 years. These findings may therefore not hold for younger women and in any
case a 3.5-year interval makes it impractical as a test for women wishing to
predict the time of the menopause.
A history of poor response
to ovarian stimulation is a further indicator of increased risk of ovarian
failure.
Nikolaou et al. [5]
reported that women who had poor response to ovarian stimulation were likely to
develop menopausal symptoms within 7 years. Lawson et al. reported that poor
ovarian response was a stronger predictor of ovarian failure than an elevated
FSH [6].
Treatment with donor eggs
remains very successful with very good pregnancy rates. The difficulty with
this treatment, however in many countries, remains the lack of donors; this
issue is discussed elsewhere in this publication.
A further aspect of the
treatment is oocyte (or embryo) cryopreservation; it is widely used for women
prior to cancer treatment and there is an increasing demand for social egg
freezing.
Egg freezing was first
carried out more than 25 years ago. However, in recent years, the success rate
of egg freezing has improved with the introduction of vitrification or fast
freezing, which is a technique that avoids ice formation within the cell. A recent
study has shown that the pregnancy rate using fresh eggs is not better than
that of using frozen eggs from donors with pregnancy rates of around 50 % in
both groups. It must be pointed out however that in this study the egg donors
in both groups were very young at 26 year so age [7].
There is increasing demand
for social egg freezing. One of the largest reports from Brussels [8] reported
that the mean age of women who store eggs for social reasons was 37. The reason
for this presumably is that women in their middle to late 30s who realize that
they will not be having children in the very near future are wishing to
preserve fertility as an insurance policy. The majority of women in this report
indicated that they expected never to have to use these frozen eggs. However,
experience of thawing is limited, particularly in this age group and only one
woman thawed her treatment with frozen/thawed eggs. She was 39 and
unfortunately did not conceive. There is more experience with post-chemo
therapy and the success here is likely to be related to the woman’s age and
health prior to any chemo or radiotherapy. Data regarding the successful
thawing of fertility treatment for women who have chemotherapy is lacking due
to the fact that women who freeze eggs prior to chemotherapy may not be in a
position to undergo fertility treatment until many years later.
More recently, there have
been reports of successful ovarian tissue freezing with autologous
transplantation. However, very few pregnancies have occurred with this
treatment and this remains experimental. The advantages, however, are obvious
in that a large number of oocytes can be stored, whereas oocyte preservation
will only be applicable for a limited number of eggs.
GnRH treatment prior to
chemotherapy has been proposed as a way of reducing the likelihood of ovarian
damage and a recent Cochrane review confirms that this can reduce the
likelihood of amenorrhoea and increase the likelihood of spontaneous ovulation.
However, there does not appear to any increase in the incidence of pregnancy
[9j.
Loss of fertility is often
the most distressing consequence of premature ovarian insufficiency and
premature ovarian menopause and indeed this diagnosis may first be identified
by infertility specialists. As women delay motherhood, an increasing number of
women with this diagnosis will require fertility treatment. There is an
increasing demand for social egg freezing but while the results of freezing
donor eggs is encouraging, there is little data regarding the outcome of social
egg freezing where women are usually older. Women needing chemotherapy or
radiotherapy may benefit from pre-treatment with Gonadotropin Releasing
Hormone. As yet there is no reliable predictor of POI.
Baber R, Abdalla H, Studd
J (2009) The premature menopause. In: Studd J (ed) Progress in obstetrics and
gynaecology, vol 9. Churhill Livingstone. London, pp 209-226
Bidet M. Bachelot A.
Bissauge E, Golmard JL. Gricourt S, Dulon J. Coussieu C. Badachi Y. Touraine P
(2011) Resumption of ovarian function and pregnancies in 358 patients with
premature ovarian failure. J Clin Endocrinol Metab 96( l2):3864-3872
Bentzen JG, Forman JL.
Larsen EC. Pinborg A. Johannsen TH, Schmidt L, Friis-Hansen L. Nyboe A (2013)
Maternal menopause as a predictor of anti-Mullerian hormone level and antral
follicle count in daughters during reproductive age. Hum Reprod 28( 1
):247—255. doi: 10. 1093/humrep/des356, Pubivled PMID: 23136135
Freeman EW. Sammel MD, Lin
H, Boorman DW, Gracia CR (2012) Contribution of the rate of change of Antimullerian
hormone in estimating time to menopause in late reproductive age women. Fertil
Steril 98(5): 1254-1259.el-e2
Nikolaou D, Lavery S,
Turner C, Margara R. Trew G (2002) Is there a link between an extremely poor
response to ovarian hyperstimulation and early ovarian failure? Hum Reprod
17(4): 1106-11II
Lawson R. El-Toukhy T,
Kassab A, Taylor A. Braude P. Parsons J, Seed P (2003) Poor response to
ovulation induction is a stronger predictor of early menopause than elevated
basal FSH: a life table analysis. Hum Reprod 18(3):527—533
Cobo A, Meseguer M. Remohi
J, Pellicer A (2010) Use of cryo-banked oocytes in an ovum donation programme:
a prospective, randomised, controlled clinical trial. Hum Reprod 25
(9):2239-2246
Oocyte Banking for
Anticipated Gamete Exhaustion (AGE): A Follow-Up Study, Stoop D. Maes E,
Polyzos NP, Verheyen G, Toumaye H, Nekkebroeck J (2013) European Society of
Human Reproduction and Embryology 29th Annual Meeting, London, United Kingdom,
7-10 July 2013
Chen H, Li J, Cui T, Hu L
(2011) Adjuvant gonadotropin-releasing hormone analogues for the prevention of
chemotherapy induced premature ovarian failure in premenopausal women. Cochrane
Database Syst Rev (11):CD008018
Premature ovarian
insufficiency (POI) remains poorly understood and underresearched [1], It
describes a syndrome consisting of early cessation of periods, sex steroid
deficiency, and elevated menopausal levels of the pituitary hormones FSH and LH
in women below the age of 40. POI can be primary (spontaneous POI) or secondary
(induced by radiation, chemotherapy or surgery). Controversy persists over
nomenclature with terms such ‘premature ovarian failure/dysfunction and
‘primary ovarian insufficiency’ still in usage.
POI has been estimated to
affect about 1 % of women younger than 40, 0.1 % under 30 and 0.01 % of women
under the age of 20. However, as cure rates for cancers in childhood and young
women continue to improve, it is likely that the incidence of prematurely
menopausal women is rising rapidly [2], Recent data from Imperial College
London suggest that the incidence of POI may be significantly higher than
originally estimated. Cartwright and Islam [3] studied 4,968 participants from
a 1958 birth cohort. They found that 370 (7.4 %) had either spontaneous or
medically induced POI. Smoking and low socioeconomic status were predictive of
POI and poor quality of life (SF 36) was twice as common in POI. The incidence
of POI also appears to vary according to the population studied. It appears to
be significantly higher, >20 %, in some Asian populations (personal communication
from Indian Menopause Society).
In the past, the focus of
medical care has been on improvement of survival rates. Very little attention
has been given to the maintenance of quality of life in the short term and to
the avoidance of the long-term sequelae of a premature menopause. One of the
main reasons for this has been the bias of economic expenditure and medical
endeavour to the prolongation of life (e.g. cancer treatments) rather than
N. Panay (El)
Queen Charlotte’s &
Chelsea and Chelsea & Westminster Hospitals, Imperial College London, Du
Cane Road, TW9 3BU London, UK e-mail: nickpanay@msn.com
© International Society of
Gynecological Endocrinology 2014, Corrected printing 2015 127
A.R. Genazzani, M. Brincat
(eds.). Frontiers in Gynecological Endocrinology:
Volume I: From Symptoms to
Therapies, ISGE Series DOI 10.1007/978-3-319-03494-2_12,
towards optimising quality
of life in cancer survivors. Should this trend continue we are in danger of
creating a population of young women who have been given back the gift of life
but left without the zest to live it to its full potential. Maintenance of
postmenopausal health is also of paramount importance if we are to minimise the
economic impact on society in this and future generations.
Causes of spontaneous POI
include idiopathic (no known cause), genetic, autoimmune and infective. The
typical presentation of spontaneous POI is erratic or complete cessation of
periods in a woman younger than 40 years, which may or may not necessarily be
accompanied by symptoms. These symptoms may not be typical vasomotor in nature
and include mood disturbances, loss of energy and generalised aches and pains.
Our data and data from others [4-6] indicate that the next most disturbing
aspect of POI after the loss of fertility is the adverse impact on sexual
responsiveness and other psychological problems.
Thus, women with POI
require integrated care to address physical, psychosocial and reproductive
health as well as preventative strategies to maintain long-tenn health.
However, there is an absence of evidence-based guidelines for diagnosis and
management. POI is a difficult diagnosis for women to accept, and a carefully
planned and sensitive approach is required when informing the patient of the
diagnosis. A dedicated multidisciplinary clinic separate from the routine menopause
clinic will provide ample time and the appropriate professionals to meet the
needs of these emotionally traumatised patients. At the West London Menopause
Centres, we have restructured our services and created a dedicated clinic for
the POI patients. Counselling at this stage should include explanation that
remission and spontaneous pregnancy can still occur in women with spontaneous or
medical POI. Specific areas of management include the provision of counselling
and emotional support, diet and nutrition supplement advice, hormone
replacement therapy and reproductive health care, including contraception and
fertility issues. There is an urgent need for large-scale long-term randomised
prospective studies to determine the optimum routes and regimens of hormone
replacement therapy. Outcome measures should include short-term symptoms,
vasomotor, urogenital and psycho- sexual and the long-term effect on
cardiovascular, cognitive and skeletal health.
As a minimum, the initial
investigation of patients presenting with erratic periods, for which pregnancy
should be excluded, include measurement of serum follicle- stimulating hormone
(FSH), oestradiol and thyroid hormones. If FSH is in the menopausal range in a
woman younger than 40, the test should be repeated along with oestradiol for
confirmation as levels can fluctuate.
Evaluation of other
hormones of ovarian origin, such as inhibin B and anti- Mullerian hormone
(AMH), and the ultrasonographic estimation of the antral follicle count are
also being used to predict ovarian reserve. Some studies suggest that the
precise age of menopause transition can be predicted through the use of these
biomarkers; this requires confirmation, especially in POI [7—9]. In the long
term, the polygenic inheritance of a risk for spontaneous POI will be
unravelled and banks of genes will be tested to give an individual the precise
risk of suffering POI.
Women diagnosed with POI
go through a very difficult time emotionally. The condition has been associated
with higher than average levels of depression. Loss of reproductive capability
is a major upsetting factor and this does not depend on whether the woman has
already had children or not. Professional help should be offered to help
patients cope with the emotional sequelae of POI. Adequate information should
be given in a sensitive manner, including information about National
self-support groups for POI, such as the Daisy Network in the UK (http:// www.daisynetwork.org.uk).
Young women with
spontaneous POI have pathologically low oestrogen levels compared to their
peers who have normal ovarian function. The global consensus on hormone therapy
[10] and updated 2013 IMS recommendations [11] state that in women with POI,
systemic hormone therapy is recommended at least until the average age of the natural
menopause (51 years).
Hormone therapy is
required not only to control vasomotor and other menopause symptoms but also to
minimise risks of cardiovascular disease [12], osteoporosis [13] and possibly
Alzheimer’s dementia [14], as well as to maintain sexual function. There is no
evidence that the results of the Women’s Health Initiative study (a study of
much older women) apply to this younger group. Hormone replacement therapy in
POI patients is simply replacing ovarian hormones that should normally be
produced at this age. It is of paramount importance that the patients
understand this in view of the recent press on HRT. The aim is to replace
hormones as close to physiological levels as possible.
Since spontaneous ovarian
activity can occasionally resume consideration should be given to appropriate
contraception in women not wishing to fall pregnant. Although standard oral
contraceptive pills are sometimes prescribed, they contain synthetic steroid
hormones at a greater dose than is required for physiological replacement and
so may not be ideal. Low dose combined pills may be used to provide oestrogen
replacement and contraception, although they are less effective in the
prevention of osteoporosis and induce less favourable metabolic changes [ 15.
16]. The progestogen intrauterine system may also be offered in those who
choose HRT and require contraception.
In our experience, the
choice of HRT regimen and the route of administration vary widely among
patients. In the absence of better data, treatment should therefore be
individualised according to choice and risk factors. Where libido is a problem,
testosterone replacement should be replaced, especially in surgically
menopausal women. Although there is an absence of licensed androgenic
preparations which can be used, off-label use of physiological female doses of
transdermal testosterone appears efficacious and safe.
To complement the role of
HRT for the long-term prevention of osteoporosis, supplementary intake of
adequate dietary calcium (1,000 mg/day) and vitamin D (800-1,000 IU/day) should
be encouraged, as should weight bearing exercises. The use of complementary
therapies and non-oestrogen-based treatments such as bisphosphonates, strontium
ranelate or raloxifene for the prevention of osteoporosis in women with POI has
not been studied.
Women with POI are not
necessarily sterile unless surgically menopausal. There is however only a 5 %
chance of spontaneous conception. Hence, women for whom fertility is a priority
should be counselled to seek assisted conception by IVF using donor eggs or
embryos. Future advances in the research of stem cells may make it possible for
some women with POI to achieve pregnancy with their own oocytes
. Until such a time,
oocyte/embryo donation remains the only real chance for these women to achieve
pregnancy by assisted conception. Another family building option that should be
discussed is adoption.
We urgently need to
determine the scale of the POI problem, initially by the trawling of data from
all clinics that manage women with POI. The data will undoubtedly demonstrate
extreme variations in management and deficiencies will emerge. Armed with this
information departments of health can then be petitioned to provide appropriate
funding for the setting up of multidisciplinary units for the management of the
particular psychological and physical needs of women with POI.
In the absence of
prospective randomised controlled data, there is a need for high-quality
observational data. There have been calls for a database/registry from our and
other units to provide this information [18, 19].
Individual centres
generally do not have sufficient exposure to women with POI to gather
sufficient observational or RCT data to give meaningful results on disease
characterisation and long-term outcomes. Cooper et al. make the point that
fragmented research leads to fragmented patient care [19]. We are in total
agreement that without definitive research, we are left to advise women with
POI using inappropriate postmenopausal practice guidelines that are based on a
different patient population.
The problems we need to
overcome in setting up this database include a lack of established standards
and design, quality of data, consistency of recruitment criteria, etc. Also,
there has to be agreement as to the nature and quantity of the sample size
required e.g. inclusion of women with iatrogenic POI as well as spontaneous.
The collaborative effort of a cohort of international centres specialising in
POI management can overcome many of these limitations.
It is vital that there is
a sense of collective ownership of the data and any publications resulting from
the research. We are currently in the process of data entry field modification
through regular workshops with key collaborators to refine data capture fields
and propose areas of data analysis and publication.
The potential benefits of
such a database are many. It could be used to create not only an information
database but also a global bio bank for genetic studies, with an ultimate goal
of defining the specific pathogenic mechanisms involved in the development of
POI e.g. unravelling the polygenic inheritance mechanism.
The database would have
the potential to define and characterise the various presentations of POI along
the lines of the STRAW + 10 Guidelines for natural menopause. The STRAW + 10
collaborators in their recent paper state that special groups, such as POI,
warrant urgent attention for staging of reproductive aging
, It could also be used to
further refine the role of biomarkers such as anti- Mullerian hormone to
precisely predict the course and timing of natural and early ovarian
insufficiency [7-9].
There is a desperate need
to determine long-term response to interventions such as the contraceptive
pill, hormone therapy and those not receiving treatment. This is particularly
important in women with rare causes and hormone-sensitive cancers where
randomised trials are unlikely to be ever performed.
Regarding treatment,
questions which urgently need to be answered include, does the type of HRT
matter, body identical versus other types of HRT, oral versus transdermal
oestrogen, dosage of oestradiol, progesterone versus retroprogesterone versus
androgenic progestogens and impact of androgens, on both short-term quality of
life and long-term outcomes. The database will also give the opportunity for
the role of unproven fertility interventions in POI to be studied such as DHEA,
and the use of ultra low dose HRT and the contraceptive pill to suppress FSH
levels to facilitate ovulation of any remaining oocytes.
As is the case with a
number of other centres, we have been collecting data from our cohort of women
with POI for a number of years (over 500 subjects to date)
. The next step is to
amalgamate these data with those of our colleagues globally. We have already
had verbal agreement from more than 30 international experts in POI who would
be willing to contribute to such a database. An online website is currently
being designed. All collaborators will have the opportunity to offer their
views on ultimate database structure and data entry fields before realtime
data entry commences in late 2013. The concept of the database has already been
launched at the 15th World Congress of Gynecological Endocrinology 2012 and the
9th European Congress on Menopause and Andropause 2012 to the universal
approval of experts and delegates [22, 23].
POI affects many young
women globally. These women have unique needs that require special attention.
There is an urgent need for standardised terminology and evidence-based
guidelines upon which to establish the diagnosis and manage this
difficult condition. These
guidelines must be drawn up from population specific data to have any relevance.
An international POl registry has the potential to provide such information.
The problems and limitations of a disease database/ registry can be minimised
with adequate consensus, communication and collaboration. We hope this will
ultimately lead to better understanding of the condition and the development of
guidelines for the strategic optimisation of health and fertility in POI.
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