Keywords
endometrial cancer - fertility - obesity - ovarian reserve - PCOS
Recently, fertility-sparing treatment has been offered to women of fertile age with
a future pregnancy wish in selected cases and under certain, strict criteria.[1] The standard treatment for endometrial cancer is total hysterectomy with bilateral
salpingo-oophorectomy, but if the cancer is early-stage and nonmetastatic or atypical
hyperplasia, nonsurgical treatment with hysteroscopic tumor resection followed by
hormonal treatment with oral progestins and/or a levonorgestrel-releasing intrauterine
device can be an alternative. This will potentially allow for a future pregnancy once
the patient has reached complete response. However, the window in which the patient
is allowed to become pregnant is short, and ultimately definitive surgery is recommended.
The purpose of this article is to highlight and discuss some of the fertility-related
problems women are faced with and how to address them.
Background
Endometrial cancer is not the most common type of cancer found in women with an age-standardized
incidence of 12.8/100,000 women in the Nordic countries,[2] but the incidence is increasing, and although not often affecting young women, it
does occur even in the age group younger than 40 years. For atypical hyperplasia,
the incidence is also very low in women of fertile age with a rate of less than 7
cases per 100,000 women in their 30s per year.[3] And for this age group, it can have devastating consequences, because of the profound
effects it can have on fertility. With the increasing trend to postpone childbearing
and the increasing age of first child, which is seen in the industrialized world,
the chance of a woman being nulliparous when diagnosed with endometrial cancer or
atypical hyperplasia is high. Infertility is seen more often in obese women and women
diagnosed with polycystic ovarian syndrome (PCOS) than in normal weight and regularly
cycling women, as is endometrial cancer. So even though a lot of these women will
have a pregnancy wish and will be candidates for fertility-sparing surgery, they may,
as illustrated in [Fig. 1], face problems in becoming pregnant, which will be discussed in this article.
Fig. 1 Fertility challenges facing women with endometrial cancer.
Ovarian Reserve Assessment
Ovarian Reserve Assessment
Before the decision is made to offer fertility-sparing treatment, the patient should
be referred to a fertility specialist for fertility assessment and individual counseling.
Many factors can contribute to an individual's fertility, and if the chance of pregnancy
is already found to be very low, she may be better off going directly for standard
surgical treatment. If, on the other hand, the patient does not have too many risk
factors associated with low fertility and she otherwise fulfills the criteria, fertility-sparing
treatment can be considered.
Menstrual Cycle Length
Regular menstrual cycles lasting 28 to 31 days are strong indicators of spontaneous
ovulation and a well-functioning hypothalamic–pituitary–gonadal axis, suggesting a
good chance of natural conception. However, women with PCOS often have anovulatory
cycles or infrequent ovulation, leading to amenorrhea or oligomenorrhea.[4] This means that her chances of conceiving spontaneously each month are severely
reduced, and time to pregnancy will often be much longer than for regularly cycling
women. This can be a problem if a short time-to-pregnancy is required. Nevertheless,
for women with PCOS there is a trend toward more cycle regularity with age, which
could improve their fertility, although the oocyte quality remains the same as for
the same-age background population. It is normal for the menstrual cycle to shorten
in the years leading up to the perimenopausal transition, and this can serve as an
early sign of declining ovarian reserve. As menopause approaches, cycles become irregular
and eventually stop. A recent systematic review and meta-analysis found that shorter
menstrual cycles (21–27 days), compared with normal cycles (28–31 days), were significantly
associated with lower anti-Müllerian hormone (AMH) levels, lower antral follicle count
(AFC), reduced fecundability, and poorer in vitro fertilization (IVF) outcomes.[5]
Basal Serum Follicle-Stimulating Hormone and Estradiol Measurement
Early-follicular-phase measurement of follicle-stimulating hormone (FSH) can be used
to detect a diminished ovarian reserve. Elevated levels on days 2 to 5 of the menstrual
cycle are a specific, but not sensitive test for a reduced ovarian reserve, but with
significant inter- and intracycle variability. Basal estradiol (E2) measurement can be used as an aid to interpret the basal FSH value correctly. An
early rise in serum E2 concentrations is seen in women with a diminished ovarian reserve, but will cause
the FSH level to drop from an elevated level to within the normal range, so a normal
FSH value concomitant with an elevated E2 concentration may still indicate a diminished ovarian reserve. However, the Practice
Committee of the American Society for Reproductive Medicine states that ovarian reserve
tests are poor predictors of reproductive potential independently from age and should
only be used as predictors of oocyte yield following controlled ovarian stimulation.[6]
Anti-Müllerian Hormone
AMH is a member of the transforming growth factor-β superfamily and is produced by
the granulosa cells of preantral and small antral follicles. It has long been recognized
as one of the best predictors we have for ovarian reserve, albeit not perfect. After
its peak values around 25 years of age, a gradual decline of around 5% per year is
seen.[7] AMH is one of the biomarkers used in the Bologna criteria for low ovarian reserve
and, more recently, in the Poseidon criteria for identifying patients who have a low
prognosis in assisted reproductive technology (ART). According to the Bologna criteria,
a low ovarian reserve is defined as having at least two of the following three criteria:
(1) an advanced maternal age, (2) a previous poor ovarian response to ovarian stimulation,
(3) an abnormal ovarian reserve test defined by an AFC of less than five to seven
follicles or an AMH level less than 0.5 to 1.1 ng/mL.[8] In the Poseidon criteria, four groups of low prognosis patients are defined, and
AMH occurs in all four definitions: group 1 includes young patients with a suboptimal/low
oocyte number, group 2 includes old patients with a suboptimal/low oocyte number,
group 3 includes young patients with an expected low oocyte number, and group 4 includes
old patients with an expected low oocyte number. Here, a low AMH is defined as less
than 1.2 ng/mL.[9]
Several studies have looked at the role of AMH in predicting outcomes after ART. One
meta-analysis that included 32 studies analyzed the relationship between AMH and cumulative
live birth rate (CLBR) after ART.[10] The authors found that serum AMH levels were linked to CLBR, although no discriminating
lower or upper threshold could be established, prompting the authors to discourage
the use of AMH as the sole criterion for rejecting IVF treatment. No predictive value
between AMH and clinical outcomes after intrauterine insemination (IUI) could be found.
Tal and co-authors found that the predictive ability for AMH and pregnancy was greatest
in women with a diminished ovarian reserve with an odds ratio (OR) of 3.96 (95% confidence
interval [CI]: 2.57–6.10).[11] The consequences of having a high AMH, which is the case for women with PCOS, have
also been assessed in relation to ART. A meta-analysis demonstrated that women with
PCOS and an AMH within the 75th to 100th percentile had a decreased odds of a clinical
pregnancy (OR: 0.77, 95% CI: 0.63–0.93) and livebirth (OR: 0.71; 95% CI: 0.58–0.87)
when compared with those within the lowest percentiles.[12] In this study, the authors also looked at the number of oocytes retrieved and fertilization
rate, and although there was an increased number of oocytes retrieved in the high
AMH group, the fertilization rate was decreased.
In non-PCOS women, on the other hand, AMH has been shown to be a poor predictor of
the chance of natural conception, even in women with a low AMH value.[13]
[14]
Antral Follicle Count
Another biomarker of ovarian reserve is the AFC. Antral follicles between 2 and 10 mms
in size are counted and the number has been found to be closely related to the total
number of primordial follicles in the ovaries.[15] A linear relationship of AFC with age has been demonstrated with a median decline
of 2.4% per year in 362 regularly cycling pre-menopausal women.[16] This was confirmed by Bentzen and co-authors who found that chronological age was
inversely related to total AFC in 366 healthy healthcare workers.[17] An interesting finding from this study was that subclasses of antral follicles sized
2 to 4 and 5 to 7 mm decreased with increasing age, whereas antral follicles sized
8 to 10 mm increased with increasing age, and the occurrence of large follicles was
more strongly related to biological age than chronological age. Comparing 228 users
of hormonal contraception with 504 non-users, AFC was found to be 30.4% lower in the
hormonal contraception group after adjusting for age, calling for caution when interpreting
ovarian reserve markers in users of hormonal contraception, which is also the case
for AMH.[18] AFC (as AMH) has been found to be a good predictor of the outcome of ovarian stimulation.
Two studies have independently found it to be an accurate predictor of excessive response
to ovarian hyperstimulation with a sensitivity of 82% and a specificity of 80%[19] and has been suggested ideal, (together with AMH) in planning personalized controlled
ovarian stimulation protocols.[20] However, AFC is not a good tool in predicting the chance of pregnancy after IVF,
as found in a meta-analysis by Hendriks et al that included 10 studies.[21]
Age
One of the most important predictors of the chance of pregnancy and live birth is
the woman's age. This is due to both the declining number of oocytes and the increasing
proportion of oocytes with chromosomal abnormalities that occur with advanced age.[22] It has long been known that as women age, endocrine changes will occur concomitant
with cycle irregularities, eventually leading to menopause.[23] A systematic review and individual participant data meta-analysis that included
4,379 women of at least 35 years of age revealed an expected natural fertility decline
with female age. The probability of natural conception significantly decreased with
any diagnosis of infertility, when compared with unexplained infertility.[24] Embryo aneuploidy is considered the most important limiting factor in the success
rates after ART. But even after performing preimplantation genetic testing for aneuploidy
and only transferring euploid embryos, there is a reduced ongoing pregnancy rate (OPR)
and live birth rate (LBR) among women older than 35 years. A recent systematic review
and meta-analysis found a higher OPR/LBR (OR: 1.29; 95% CI: 1.07–1.54) in women <35
years than in women ≥35 years with a risk difference equal to 0.06 (95% CI: 0.02–0.09),
suggesting that other factors as well play a part in the reduced chance of a live
birth in older women.[25] This is supported by a retrospective cohort study evaluating implantation rate (IR)
after 8,175 euploid embryo transfers from a single center. All women had single embryo
transfer, and prior to transfer all women underwent uterine cavity evaluation to exclude
any anatomical abnormalities. Patients were divided into five age groups: <35 years
old (n = 3,789 embryos transferred), 35 to 37 (n = 2,200), 38 to 40 (n = 1,624), 41 to 42 (n = 319), and >42 (n = 243). Again, the authors found that IR negatively correlated with age. Women 38
years or older had a significantly lower IR than those under 35 (OR: 0.85, 95% CI:
0.73–0.99 for 38–40 years old; 0.69, 0.53–0.91 for 41–42, and 0.69, 0.51–0.94 for > 42).[26]
Another factor to consider when explaining the reduced fertility that comes with advanced
maternal age is the endometrium and its ability to allow for implantation and sustain
a pregnancy. Studies have shown that there might be an association between a decline
in endometrial receptivity and advanced maternal age.[27] In an oocyte donation program using either intended parent recipients or gestational
carriers, the odds of a clinical pregnancy were significantly higher when using a
gestational carrier (65.2 vs. 56.3%, adjusted OR [aOR]: 1.33, 95% CI: 1.17–1.51),
which was also the case for live birth (57.1 vs. 46.4%, aOR: 1.37, 95% CI: 1.21–1.55).[28] But further studies are needed.
Together, all these studies show that age is an important factor to take into consideration
before offering fertility-sparing treatment to women with early-stage endometrial
cancer, even if they want to use donor eggs.
Obesity
Overweight and obesity are an increasing problem all over the world. It affects nearly
two in five adults globally and is no longer a problem solely concerning the industrialized
world.[29] It has huge economic- and health-related consequences, not only on an individual
basis but also for the society. It contributes to numerous diseases, including cancer.
With this growing trend of more and more people becoming obese, particularly among
the younger population, more cases of endometrial cancer are to be expected in women
of fertile age in the future. Obesity also affects fertility. The ovarian reserve
markers AMH and AFC have been found to be significantly lower in obese women when
compared with non-obese women, indicating reduced fertility.[30] A very recent systematic review and meta-analysis found that female overweight and
obesity are associated with an increased risk of subfecundity (OR = 1.44; 95% CI:
1.20, 1.72) and infertility (OR = 1.60, 95% CI: 1.31–1.94).[31] And it does not seem that ART can circumvent this. Turner et al found in their meta-analysis
that overweight and obese women, who were otherwise healthy and with no comorbidities,
still were less likely to attain a clinical pregnancy, if their BMI was >25 (OR: 0.76,
95% CI: 0.62–0.93, p = 0.007), and even more so with a BMI >30 (OR: 0.61, 95% CI: 0.39–0.98, p = 0.04) when using ART.[32] They also required more days of stimulation and achieved fewer oocytes than women
with a normal BMI. Other studies support these findings.[33]
[34]
The Role of Lifestyle Change
With the knowledge we have of reduced fertility in overweight and obese women, it
is obvious to encourage lifestyle changes. Measures such as reduced caloric intake,
healthier diet, increased aerobic exercise, and adaptation to a less sedentary lifestyle
should be encouraged as the first choice. However, these measures do not always lead
to the desired weight loss and can sometimes be difficult to adhere to in the long
run. A prospective, randomized controlled trial including 317 women < 38 years of
age with a BMI of >30 and <35 from Denmark, Iceland, and Sweden found no statistically
significant difference in LBR between those randomized to weight reduction on a low-caloric
diet 3 months prior to IVF and the control group without weight loss.[35] Modern weight loss drugs such as the glucagon-like peptide-1 receptor agonists (GLP-1)
or bariatric surgery may be an alternative. Although for obese patients, lifestyle
intervention studies leading to weight loss have many beneficial consequences to their
general health, there seems to be little to no effect on fertility for some reason.[36]
[37]
[38] In any case, patients with endometrial cancer who have obtained complete remission
rarely have the time to lose weight before trying to conceive; so, lifestyle advice
should ideally be given at the time of diagnosis rather than at the time of complete
remission.
Polycystic Ovarian Syndrome
Polycystic Ovarian Syndrome
PCOS is a condition defined by ovulatory dysfunction causing irregular menstrual cycles,
hyperandrogenism, and polycystic ovaries (at least two of these three criteria should
be present) according to the Rotterdam criteria.[39] It is believed to affect 5 to 20% of reproductive-aged women worldwide. Although
not perfect, recent guidelines and reviews still recommend using the Rotterdam criteria
in the diagnosis of PCOS.[40]
[41] In general, women with PCOS are found to have higher levels of serum AMH and higher
AFC than women not diagnosed with PCOS, indicating a higher ovarian reserve[42]; however, as discussed above, this is not always an advantage when a short time
to pregnancy is desired. A higher risk of developing endometrial cancer has been found
in women with PCOS.[43] Factors such as elevated estrogen for a longer period of time, type-2 diabetes,
obesity, and persistent thick endometrium, all associated with PCOS, can all individually
act as risk factors for developing endometrial cancer. However, one study found that
when adjusting for BMI, the association between PCOS and endometrial cancer was no
longer found.[44] A recent comprehensive review on the endometrial function of women with PCOS found
evidence to support the presence of an “endometrial factor” related to subfertility
and poor pregnancy outcomes in these women.[45] This can in part be explained by the hyperestrogen and hyperandrogen responsiveness
of the endometrium and the progesterone resistance on top of an inhospitable and inflammatory
environment leading to abnormal trophoblast invasion and placentation, miscarriage,
and pregnancy complications.
Use of Metformin
Metformin is an antihyperglycemic biguanide drug used in the treatment of type 2 diabetes
mellitus. It inhibits hepatic gluconeogenesis and reduces the action of glucagon,
thus reducing the levels of circulating insulin and glucose. This could be beneficial
for women with PCOS, as their increased insulin resistance, hyperandrogenism, and
obesity all have an impact on menstrual cyclicity and thus fertility. The hope is
that treating women with PCOS with metformin will lead to more ovulatory cycles and
increase the chance of natural conceptions. A Cochrane review found that metformin
may improve LBRs compared with placebo (OR: 1.59, 95% CI: 1.00–2.51). The metformin
group had higher rates of clinical pregnancies (OR: 1.93, 95% CI: 1.42–2.64), ovulation
(OR: 2.55, 95% CI: 1.81–3.59), and menstrual frequency (OR: 1.72, 95% CI: 1.14–2.61).[46] In non-obese women with PCOS, treatment with metformin also seems to have some effect
on the clinical pregnancy rate. A systematic review and meta-analysis of 21 RCTs including
2638 normal-weight women with PCOS found a slight increase in clinical pregnancy rate
compared with placebo (47.7 vs. 42.9%) (pooled risk ratio = 1.08 [0.82, 1.42], 95%
CI, p = 0.60), results being comparable to clomiphene citrate.[47]
An alternative use of metformin is to reverse endometrial hyperplasia, although the
evidence of its beneficial effect remains uncertain. In a Cochrane review, the authors
found insufficient evidence to support or refute the use of metformin in the treatment
of atypical endometrial hyperplasia, calling for better-designed randomized controlled
trials with long-term outcome.[48]
Lynch Syndrome
Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer, is a hereditary
autosomal dominant disorder that increases the risk of many types of cancer such as
endometrial cancer. Women with Lynch syndrome have a higher overall risk of developing
cancer than men, and some of these women will still be of reproductive age and wish
a pregnancy. However, the risk of passing on the gene to a child is of great concern,
and for some preimplantation genetic testing for monogenic/single-gene disorders (PGT-M)
could be an option.[49] Obviously, women carrying the gene should ideally become pregnant before the onset
of a cancer, but the condition is often underdiagnosed, which could explain the so
far low use of PGT-M for this specific condition. But PGT-M can be time-consuming,
and, as such, may not be a realistic option for patients already diagnosed with endometrial
cancer.
Conclusion
Young women diagnosed with early-stage endometrial cancer or atypical hyperplasia
are often also challenged with factors predisposing to infertility or subfertility.
This can further complicate their chances of conceiving in the short period after
complete remission has been obtained, during which they are allowed to become pregnant.
PCOS is associated with an increased risk of endometrial cancer, and with PCOS there
is an increased risk of anovulation and obesity. This may require the use of ART to
shorten the time to pregnancy, but even with ART the pregnancy rates and delivery
rates are reduced in obese women as compared with normal-weight women. Age is also
a risk factor associated with infertility. A reduced ovarian reserve and an increased
risk of aneuploidy in the remaining oocytes are seen with increasing age. This reduces
the pregnancy rates and delivery rates, something that cannot be compensated by ART.
So, in conclusion, women who are candidates for fertility-sparing surgery should be
selected carefully, and healthcare professionals should be aware of the underlying
infertility issues that these women are often faced with.
