Best Practice & Research Clinical Endocrinology & Metabolism 29 (2015) 105e114

Contents lists available at ScienceDirect

Best Practice & Research Clinical

Endocrinology & Metabolism
journal homepage: www.elsevier.com/locate/beem

Sex hormone replacement in ovarian failure e

new treatment concepts
Jenifer Sassarini, MBChB, Clinical Lecturer a,
Mary Ann Lumsden, BSc, MBBS, MD, Professor of Medical
Education and Gynaecology a,
Hilary O.D. Critchley, BSc, MBChB, MD, Professor of
Reproductive Medicine b, *
a
Obstetrics and Gynaecology, School of Medicine, College of Medical, Veterinary and Life Sciences,
University of Glasgow, G31 2ER, United Kingdom
b
MRC Centre for Reproductive Health, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom

Keywords:
Premature ovarian failure is associated with decreased bone mass and
premature ovarian failure fractures, and an increased risk of premature death from cardiovas-
physiological sex steroid replacement cular disease. There is also fertility compromise associated not only
uterine morphology with the loss of ovarian function but, in those with pre-pubertal POF,
cardiovascular inadequate uterine morphology. A wide variety of hormone replace-
bone ment regimes are reported, but there is no clear evidence of best
breast practice. Hormone replacement therapy (HRT) and the combined oral
contraceptive pill (COCP) will suppress menopausal symptoms;
however neither is designed to achieve physiological replacement of
oestrogen and progesterone. There is evidence that physiological sex
steroid replacement is superior to standard hormone replacement, in
improving uterine volume as well as an improved blood pressure
profile and bone mineral density. Sex steroid replacement therapy is
long-term in these women, and therefore it is essential that the risk
benefit ratio is optimal to maximise longer term health.
© 2014 Elsevier Ltd. All rights reserved.

* Corresponding author. MRC Centre for Reproductive Health, The Queen's Medical Research Institute, 47 Little France
Crescent, Edinburgh EH16 4TJ, United Kingdom. Tel.: þ44 (0) 131 242 6858; Fax: þ44 (0) 131 242 6441.
E-mail addresses: jenifer.sassarini@glasgow.ac.uk (J. Sassarini), maryann.lumsden@glasgow.ac.uk (M.A. Lumsden), hilary.
critchley@ed.ac.uk (H.O.D. Critchley).

http://dx.doi.org/10.1016/j.beem.2014.09.010
1521-690X/© 2014 Elsevier Ltd. All rights reserved.
106 J. Sassarini et al. / Best Practice & Research Clinical Endocrinology & Metabolism 29 (2015) 105e114

Introduction

Premature ovarian failure (POF) occurs in 1 in 100 women under the age of 40, and in 90% of women
the aetiology will be undetermined [1]. Secondary failure is becoming more important as survival
following treatment for malignancy improves [2]. Sex steroid hormone replacement until the average
age of natural menopause is advised, particularly for maintenance of bone mass [3]. Cardiovascular risk
must also be considered, and in women with pre-pubertal ovarian failure, optimal uterine develop-
ment is vital to future fertility prospects. A wide variety of sex steroid replacement regimes are re-
ported, but there is no clear evidence of best practice. There is evidence demonstrating improvements
in uterine morphology with physiological sex steroid replacement (pSSR) when compared to standard
replacement regimes [4] and data are emerging revealing potential differences in cardiovascular risk
and bone protection [5,6].

Premature ovarian failure (POF)

POF occurs as a result of the loss of normally functioning ovaries. This may be as a result of
dysfunctional ovarian follicles or a decline in primordial follicles. The difference, however, is academic,
as to distinguish between the two would require ovarian biopsy, and even in the absence of follicles on
biopsy, pregnancy has occurred [7].
POF is also referred to as premature menopause, and naturally occurring menopause occurs as a
result of decreasing numbers of primordial follicles available for recruitment, with subsequent
decreased production of ovarian sex steroid hormones, resulting in loss of the normal hypothalamic,
pituitary, gonadal feedback loop. Women become oligomenorrhoeic and eventually amenorrhoeic. The
terminology surrounding POF has met with some debate, as neither POF nor premature menopause is
accurate. Both convey that the process is irreversible, which in some, it is not. Up to 50% of young
women with spontaneous POF experience intermittent and unpredictable ovarian function [8],
although there is only a 5e10% chance of spontaneous conception [9]. Additionally, the term premature
ovarian failure conveys that the woman has failed in some way and may be considered offensive.
Premature ovarian insufficiency (POI) is increasingly used, as this describes impaired ovarian function
on a continuum [10], which may be transient or progressive, rather than defining a specific endpoint,
however, consensus is yet to be reached. For the purpose of this paper, we will use the term POF.

Aetiology

POF occurs in 1 in 100 women under the age of 40 [11], 1 in 1000 women under the age of 30, and 1
in 10 000 women under the age of 20 and it can be primary or secondary [12]. Primary POF may occur
in women at any age, and can present as primary or secondary amenorrhoea. Secondary POF is
becoming more important as survival improves following treatment for malignancy through surgery,
chemotherapy and radiotherapy.
Causes of POF are shown in Table 1 [7].

Table 1
Causes of POF [12]. Reproduced with permission from Elsevier.

Primary
Chromosome abnormalities (X chromosome; Down Syndrome)
FSH receptor gene polymorphism and inhibin B mutation
Enzyme deficiencies (Galactosaemia; 17a-hydroxylase deficiency)
Autoimmune disease
Secondary
Chemotherapy and radiotherapy
Bilateral oophorectomy or surgical menopause
Hysterectomy without oophorectomy/uterine artery embolisation
Infection e.g. mumps
 J. Sassarini et al. / Best Practice & Research Clinical Endocrinology & Metabolism 29 (2015) 105e114 107

Primary (spontaneous) POF most commonly presents as secondary amenorrhoea, and most of these
women will have a normal karyotype, also described as 46XX spontaneous POF [1]. In 90% of these
cases no cause will be found (idiopathic), but in six percent there will be mutations in the FMR1 gene,
the gene responsible for fragile X syndrome, and the most common cause of familial mental retar-
dation. Specific genetic testing for FMR1 is available [13].
Other translocations, deletions, inversions and duplications on the X chromosome are also asso-
ciated with POF, and whilst accurate diagnosis of these is not essential for decision making regarding
the patient, these can be associated with infertility [8].
Presentation with primary amenorrhoea is associated with an abnormal karyotype in 50% of cases
[14] and pre-pubertal ovarian failure is most commonly associated with Turner syndrome (45XO) and
gonadotoxic treatment of childhood cancer [15].
Autoimmune disorders can be associated with POF; and in those with autoimmune POF, there is
also an association with hypothyroidism (25%), Addison's disease (3%) and diabetes mellitus type 1
(2.5%) [7].
Hysterectomy without oophorectomy may induce ovarian failure [16], although the aetiology is
uncertain, and women should be appropriately counselled.

Diagnosis

POF is diagnosed if cessation of menstruation occurs in women at an age that is more than 2
standard deviations below the average age of menopause for that population [17]. In the UK, the
average age of menopause is 51 years, and a diagnosis of POF is generally accepted to be in women who
are below the age of 40 years [12]. Early menopause is a term used if age is greater than 40 years but
less than 45.
Whilst POF is characterised by amenorrhoea, deficiency in sex steroid hormones, and elevated
levels of gonadotrophins, definitive criteria for the diagnosis do not exist [3].
Duration of amenorrhoea varies somewhat across the literature, Tibiletti describes the criteria for
POF in their study as amenorrhoea for greater than six months and FSH greater than 40IU/l [18]. A
statement released by the European Menopause and Andropause Society suggests that the diagnosis is
confirmed with an elevated FSH >40IU/L and an oestradiol level below 50 pmol/L [12], but no comment
was made on the duration of amenorrhoea. The most commonly applied definition is four months of
amenorrhoea, with serum levels of FSH greater than 40IU/L on two occasions.
One report found that more than 50% of women who presented with secondary amenorrhoea saw
three or more clinicians before laboratory testing was performed to make a diagnosis [19]. It has since
been proposed that appropriate initial investigations should be initiated following three or more
consecutive months of loss of menstrual regularity [8].

Management

It is widely accepted that the mainstay of treatment of POF is hormone replacement therapy (HRT),
at least until the average age of menopause. In addition, concerns regarding the potential risks of using
HRT, following Women's Health Initiative (WHI) and the Million Women Study (MWS) publications, in
this group of women, have all but been eradicated, as results from these studies are not applicable to
women under the age of 40.
It is recognised that early menopause is associated with increased morbidity and mortality [15].
These women have an increased risk of premature death, mainly from cardiovascular disease, and POF
has a potentially devastating effect on bone, with a reduction in bone mineral density, osteoporosis,
and increased risk of fracture. Other causes of morbidity include dementia, cognitive decline and
Parkinsonism [20e22].
Treatment of these women should be multidisciplinary, with consideration given to prevention of
potential morbidities, reproductive healthcare including fertility and contraception and the provision
of counselling and emotional support. Ideally, these women should be seen in dedicated clinics [8],
with ease of access to a multidisciplinary team.
108 J. Sassarini et al. / Best Practice & Research Clinical Endocrinology & Metabolism 29 (2015) 105e114

Pre-pubertal POF and the uterine response

Induction of puberty is required in young women with pre-pubertal POF, to facilitate the pubertal
growth spurt as well as for development of secondary sexual characteristics. There is substantial ev-
idence that growth hormone treatment increases stature in patients with Turner's syndrome [23e25],
but oestrogen replacement therapy was withheld until the mid-teens because of the view that early
oestrogen reduces adult height by accelerating epiphyseal fusion [26,27]. However, this is no longer
standard practice [28]. Oestrogen or sex steroid replacement (SSR), using ethinyloestradiol, is given to
mimic natural increases in oestrogen levels with step-wise increases over 3 years. There is increasing
use of transdermal matrix patches with natural oestrogens, again in a step wise manner, with a gradual
increase in the dose. The use of natural oestrogen replacement to induce puberty has potential benefits
on growth and breast development, but there are no good multi centres studies. COCP would be
considered for post pubertal induction, as this is considered to be ‘peer friendly’, or with HRT for-
mulations, however, consensus is yet to be reached and optimal treatment regimens are still uncertain.
A wide variety of regimes are reported in post-pubertal young women, but, again, there is no clear
evidence of best practice [29]. HRT will suppress menopausal symptoms, particularly, although not
exclusively, vasomotor symptoms and vaginal atrophy and the COCP will achieve similar results, but
neither is designed to achieve physiological replacement of oestrogen and progesterone.
In girls who require pubertal induction, these treatments are sufficient for secondary sexual
development, but uterine morphology is often unsatisfactory with failure to achieve normal volume
and configuration, and often a low success rate on oocyte donation programmes [30]. Endometrial
thickness and uterine blood flow have also been reported to be inadequate [31].
Fertility preservation is one of the most important issues for young women with POF, and opti-
misation of uterine morphology together with a functioning hypothalamic-pituitary-gonadal axis is
vital.
Physiological SSR (pSSR) consisting of transdermal oestradiol (Estraderm 50) increased stepwise to
three patches, changed twice weekly, with progesterone commenced at day 14, either orally or vagi-
nally (100 mg thrice daily), achieves sex steroid serum concentrations similar to concentrations in
women with normal ovarian function [32] and improves parameters of uterine function [33].
Furthermore, endometrial sampling has demonstrated a functional response to pSSR [31,32].
More recently, in the largest randomised trial to date, comparing pSSR with standard SSR (sSSR) in
women with POF, increased endometrial thickness (5 mm) has been demonstrated within three
months of pSSR treatment, compared to sSSR (Table 2) [4]. The pSSR regimen used was a combination
of Estraderm TTS patches and Cyclogest (progesterone) vaginal pessaries, whilst the sSSR used was
Loestrin 30 (ethinyloestradiol 30 mg and norethisterone 1.5 mg daily). Uterine volume was also
increased, although this was not statistically significant, and there were no differences in doppler
ultrasound measurement of uterine blood flow.
There is some evidence, however, that the underlying aetiology of POF may play a role in the
effectiveness of pSSR. Uterine blood flow has been shown to be increased in women with Turner
syndrome after treatment with pSSR when compared to women after surgical removal of ovaries [34].
Age too, may play a role in response to treatment. Following three months of pSSR, a smaller in-
crease in uterine volume was demonstrated in one women who had total body irradiation (TBI) before

Table 2
Overall mean with SE for each treatment regimen and difference between treatments regimens with 95% CI. Reproduced with
permission (Ref. [4]).

Uterine end points Model-adjusted meana (SE) Treatment effect

Physiological SSR Standard SSR Differenceb (95% CI) P-value

Endometrial thickness (mm) 4.8 (0.38) 3.0 (0.41) 1.8 (0.7e2.8) 0.002
Uterine volume (cm3) 24.8 (1.9) 20.6 (2.0) 4.2 (0.4e8.7) 0.070
Uterine artery resistance index 0.89 (0.013) 0.90 (0.014) 0.01 (0.03e0.01) 0.39
Uterine artery pulsatility index 3.04 (0.20) 3.24 (0.21) 0.20 (0.56e0.17) 0.27
a
Overall mean using assessments at 3, 6 and 12 months.
b
Difference is physiological SSR minus standard SSR.
 J. Sassarini et al. / Best Practice & Research Clinical Endocrinology & Metabolism 29 (2015) 105e114 109

puberty, when compared to an average response in other women who were exposed to radiation post-
puberty [35]. Exposure to abdominal irradiation for malignancy in childhood resulted in a poor uterine
response to pSSR when compared to treatment in women who had absent ovarian function for other
reasons [33].
Despite uterine volume and endometrial thickness not achieving levels seen in a normal population
of women of reproductive age, this treatment response may still be worthwhile in those seeking
fertility treatments. There have been reports of successful pregnancies resulting from cycles with
endometrial thickness less than 4 mm [36,37], and it has been suggested by the authors that short
regimes prior to fertility treatment in order to optimise uterine parameters for embryo transfer may be
beneficial [4]. There is a need, however, for larger clinical studies to ascertain the optimal regime in
young women in the context of fertility enhancement.

Cardiovascular consequences

Coronary heart disease is the most common cause of death in women after the age of 60 years [38],
but is uncommon before this age. However, women with untreated premature menopause and women
with Turner syndrome are at increased risk of coronary heart disease [39e41], and ischaemic heart
disease mortality is 2% lower with each increasing year of age at menopause [15].
Menopause has been considered to be an independent risk factor for cardiovascular disease, and is
included in the Framingham model of cardiovascular risk [42]. Metabolic alterations resembling
‘metabolic syndrome’ are associated with menopause, however there has been some debate as to
whether the increased risk of cardiovascular disease around the time of the menopause, is as a result of
the menopause per se (oestrogen deficiency) or as a result of chronological ageing.
In epidemiological studies, high total cholesterol, high LDL cholesterol, and high triglycerides have
been shown to be associated with menopausal status, but more recently, in the Study of Women's
Health Across the Nation (SWAN) [43], increases in total cholesterol, LDL, and Apolipoprotein B have
been shown to be directly related to final menstrual period, independent of age or ethnicity. This would
appear to support menopause as an independent risk factor by way of alterations in lipids associated
with increased cardiovascular risk, whilst increases in blood pressure and weight gain appear to be
linear and may reflect chronological ageing [44,45].
Fewer calcifications in the aorta [46], and less extensive atherosclerosis have also been demon-
strated in women with later menopause [47].
Early observational studies in peri- and postmenopausal women suggested that HRT was car-
dioprotective [48,49], however placebo controlled trials did not confirm this [50e52], and in fact, the
Women's Health Initiative (WHI) study was stopped early as a result of an increase in cardiovascular
events associated with the use of combined HRT. Subsequent combined analysis of the two arms of this
study (E þ P and E alone) revealed no significant effect of HRT on coronary events, and in those women
who commenced HRT within 10 years of menopause, there were fewer cases seen here compared to
controls [53]. Furthermore, a recent re-analysis of this study revealed that younger women who
commenced HRT closer to menopause had lower coronary calcium scores [54].
It would appear, from the available evidence, that there is no increase in cardiovascular events
associated with the use of HRT in young women starting HRT close to the menopause. There may even
be a protective effect, the ‘window of opportunity’, however, these women are still 10 or more years
older than women with POF, and the long-term cardiovascular effects of prolonged HRT on these
younger women use is largely unknown.
WHI used conjugated equine oestrogens (CEE) 0.625 mg daily in hysterectomised women and CEE
0.625 mg combined with medroxyprogesterone acetate (MPA) 2.5 mg in non-hysterectomised women.
Increased thrombogenesis and abnormal cardiovascular remodelling are dose dependent, and it may
be that this dose was inappropriately high for older postmenopausal women.
The oral contraceptive pill, with supra-physiological levels of sex hormones, is often used as sex
hormone replacement therapy in POF, and whilst this is effective at treating symptoms of oestrogen
deficiency, it has been linked to increases in blood pressure and associated outcomes of stroke and
subarachnoid haemorrhage [55]. Long-term use may carry significant cardiovascular risk.
110 J. Sassarini et al. / Best Practice & Research Clinical Endocrinology & Metabolism 29 (2015) 105e114

It is widely accepted that transdermal oestrogen carries a lower risk of stroke and venous throm-
boembolism (VTE) than oral administration [56], however the effect of the type of preparation on
cardiovascular risk is only just beginning to emerge.
A large body of evidence from animal studies is consistent with the hypothesis that oestrogens have
cardioprotective functions such as vasodilation [57] however, MPA partially antagonises the beneficial
effects of oestrogen on coronary artery atherosclerosis in monkeys, whereas progesterone has neutral
effects [58]. Treatment with progesterone in ovariectomised rats restored endothelial control of
vascular tone, MPA did not [59].
The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial looked at the effects of oestrogen
or oestrogen/progestin regimes (CEE 0.625 mg daily, alone or in combination with MPA 2.5 mg daily,
MPA 10 mg day 1e12, or micronised progesterone 200 mg day 1e12) on heart disease risk factors in
postmenopausal women aged between 45 and 64 years. Unopposed oestrogen was most favourable,
but for those women with a uterus, the addition of micronised progesterone did not affect blood
pressure or insulin levels, and had the most favourable outcome on HDL [60].
The Kronos Early Estrogen Prevention Study (KEEPS), HRT and cardiovascular risk in early meno-
pause, supported these findings. The addition of micronised progesterone to transdermal oestradiol or
CEE had a neutral impact on coronary calcium scores, intima media thickness, blood pressure, and lipid
and insulin resistance [61].
Neither of these studies assessed the effects in women under the age of 40 years, however, a recent
study evaluating physiological sex steroid replacement (100 mg oestradiol daily for week 1, and 150 mg
for weeks 2e4 and progesterone 200 mg twice daily for weeks 3 and 4) demonstrated lower systolic
and diastolic blood pressures in a 12-month treatment period when compared to standard regime
(ethinylestradiol 30 mg and norethisterone 1.5 mg daily for weeks 1e3) [5]. Although no differences in
arterial stiffness were demonstrated, there were reduced serum creatinine concentrations, and lower
plasma angiotensin II, suggesting better renal function and less activation of the renin-angiotensin
system, likely to be important in long-term cardiovascular outcome.
A further study has yet to publish its results of a randomised controlled trial investigating the effects
of transdermal oestradiol with either micronised progesterone or MPA on vascular elasticity, lipid
profiles, coagulation and satisfaction in women with POF [62].
Langrish [5] acknowledges that the aetiology of POF may play a role in the response to the inter-
vention. Women with Turner syndrome have an increased incidence of cardiovascular abnormalities
and women with POF as a result of radiotherapy or chemotherapy may have resultant cardiotoxicity or
underlying vascular dysfunction [63].

The impact on bone

The National Osteoporosis Society list POF as the second most important medical condition asso-
ciated with an increased risk of osteoporosis. Women aged 16e40 years with past or current ame-
norrhoea have been shown to have bone mineral density (BMD) 15% less than age-matched controls
[64]. In addition bone loss appeared to be related to the duration of amenorrhoea, and those with a
history of fracture had lower BMD than those with no fracture history. Within 18 months of diagnosis,
50% of women with POF will have significant BMD reduction, and two-thirds will be high risk for hip
fracture [65].
The accrual of bone mass in childhood is paramount to prevention of osteoporosis later if life, it has
been reported that 60% of the risk of osteoporosis can be explained by the amount of bone mass
accrued during this time [66]. Maximising bone mass during this time may be an important goal for the
prevention of osteoporosis. An increased risk of fracture has been reported in Turner syndrome [6], and
there is evidence that oestrogen replacement and treatment of short stature with growth hormone will
improve bone mass [67].
The menopause has an adverse effect on bone over time; and although there is evidence from
randomised controlled trials, including WHI, that HRT reduces the risk of spine, hip and other osteo-
porotic fractures [68], there is little research in POF.
Bone conserving doses of oestrogen were, traditionally, 2 mg oestradiol, 0.625 mg CEE or 50 mcg
oestradiol patch, and that continuous, lifelong use was required, but more recently, it has been
 J. Sassarini et al. / Best Practice & Research Clinical Endocrinology & Metabolism 29 (2015) 105e114 111

suggested that lower doses can preserve bone mass [69] and that treatment at the time of menopause
may have a long-term effect on fracture prevention [70].
Although recommendations from regulatory authorities state that HRT should not be used as a
standard first line treatment for the prevention of osteoporosis in postmenopausal women, oestrogen
remains the treatment of choice in women with POF [71]. This is widely accepted, however, there is no
consensus on the optimum replacement regime or route of delivery for these women.
Indeed, a Danish observational study demonstrated a higher incidence of osteoporotic fractures in
women with Turner syndrome when compared to controls, despite long-term hormone replacement
[72]. HRT preparations were not described, and increased fractures in this group may be as a result of
failure to reach optimal peak bone mass, however, differences have been seen in uterine parameters
[4], as well as blood pressure, and renal function [5], with physiological sex steroid replacement (pSSR)
when compared to standard hormone replacement therapy (sHRT).
Improved lumbar spine BMD has been demonstrated after 12 months of pSSR, when compared to
standard HRT (sHRT), although no difference was detected in femoral neck and total hip scores. pSSR and
sHRTsuppressed bone turnover, but only pSSR was associated with increase in bone formation markers [6].
In this study sHRT comprised ethinyloestradiol 30 mg and norethisterone 1.5 mg daily (Loestrin e a
combined oral contraceptive pill) for weeks 1e3 followed by a 7-day pill free interval. Whilst this is
clearly not a standard postmenopausal hormone replacement regimen, it was chosen after a small
survey of HRT regimens used by paediatric endocrinologists for young women with POF revealed it to
be the most popular choice [73]. The absence of improvement in bone formation markers with this
standard HRT may have implications for its long-term use; however the authors acknowledge that a 12
month study is perhaps insufficient to assess BMD changes in response to treatment. Longer-term
studies are thus required.

Sex steroid replacement and the breast

There is no evidence that oestrogen replacement increases the risk of breast cancer to a level greater
than that found in normal menstruating women, and women with POF do not need to start
mammographic screening early [12]. Those women with a family history of breast cancer should be
assessed on an individual basis.
It would appear, however, that not all progestagens are equal in terms of potential risk. In a study
investigating risk biomarkers for breast cancer in a primate model, E2 with MPA resulted in greater
proliferation in lobular and ductal breast epithelium compared to placebo, E2 with micronized pro-
gesterone did not [74].
Investigation into gene expression in the breast of cynomolgus monkeys demonstrated that genes
related to epidermal growth factor receptor (EGFR) activity were higher after E2þMPA and not after
E2þprogesterone, suggesting that proliferation may be mediated in part by EGFR activity [75].
Normal human breast cells in vitro demonstrated differences in gene expression between E2 þ MPA
and E2 þ progesterone, with the latter being associated with enriched expression of cellular function
and maintenance, and the former with cell death [76].
Although not applicable to women with POF, the Million Women Study (MWS) of postmenopausal
women described a higher risk of invasive breast cancer with oestrogens and synthetic progestagens
than with other HRT regimes in current HRT users. Micronized progesterone does not appear to in-
crease the risk of breast cancer compared with never users, however oestrogens with synthetic pro-
gestagens, including dydrogesterone, did [77].

Summary

Physiological SSR (pSSR) appears to improve uterine morphology and parameters of uterine func-
tion; however both age at POF and underlying aetiology appear to play a role in the success of the
treatment. Despite not reaching normal limits, these improvements may still be worthwhile in those
seeking fertility treatments, although larger studies are required.
pSSR (transdermal oestradiol and cyclogest (progesterone) vaginal pessaries) has been shown to
lower systolic and diastolic blood pressures when compared to a standard regimen (Loestrin;
112 J. Sassarini et al. / Best Practice & Research Clinical Endocrinology & Metabolism 29 (2015) 105e114

ethinyloestradiol 30 mg and norethisterone 1.5 mg daily), and may therefore carry fewer potential
cardiovascular risks, but again results may be dependent on the underlying aetiology of POF.
Women with POF are at significant risk of osteoporosis and related fractures. They have lower bone
mineral density than their age-matched contemporaries and those with pre-pubertal POF are partic-
ularly at risk. Improvements in lumbar spine BMD with pSSR compared to standard regimens might
suggest that pSSR is superior; however longer-term studies are required in order to draw reliable
conclusions.
There is no evidence that oestrogen replacement increases the risk of breast cancer to a level greater
than that found in normal menstruating women, and in the absence of other risk factors, women with
POF do not need to start mammographic screening early.

Practice points

 Obtain a detailed family history

 Exclude pregnancy
 Appropriate evaluation should be considered in women who are amenorrhoeic for 3 or more
consecutive months
 Initial investigations should include; serum follicle stimulating hormone (FSH), luteinising
hormone (LH), oestradiol, thyroid stimulating hormone (TSH) and prolactin
 Anti-Mullerian hormone (AMH) may be considered in these women for the assessment of
follicular reserve
 Hormone replacement therapy should be used at least until the average age of menopause
 Consider that COC may not be the best choice despite being peer friendly’
 Breast screening at an earlier age than current screening programme advises, should be
assessed on an individual basis

Acknowledgements

We wish to thank Mrs Sheila Milne for assistance with manuscript preparation and Dr Louise Bath
for her most helpful comments on the manuscript content.

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