The stages of menopause 

Natural menopause does not happen instantly; it is a gradual transition that can occur over multiple years. Diagnosed when a woman has not menstruated for one year, menopause includes three stages - perimenopause, menopause proper, and postmenopause. Toward the end of a woman’s reproductive years, she will enter perimenopause, which can last several years (Table 1). The median age at which an individual has her final menstrual period is 51.4 years.ⁱ Once menopause occurs, a woman is said to be in the postmenopausal stage. Therefore, menopause and postmenopause are synonymous for the purposes of this article.ⁱⁱ

Menopause can also be induced surgically if the ovaries are removed through a procedure known as an oophorectomy. An oophorectomy will only induce menopause if both ovaries are removed (bilateral oophorectomy), as this causes an abrupt onset of menopausal symptoms, compared to the gradual progression of natural menopause.  

When the loss of normal ovarian function due to diminished ovarian reserve occurs prior to the age of 40, this is considered premature ovarian insufficiency (POI). It is often referred to as premature or early menopause in layman’s terms.  Approximately 1 percent of women under age 40 and 0.1 percent of women under age 30 are diagnosed with POI. There are many different causes of POI, including genetic and non-genetic conditions. Some of the non-genetic conditions that can cause POI include autoimmune disorders, metabolic disorders, infection, environmental causes, and iatrogenic causes (i.e., chemotherapy or radiation).ⁱⁱⁱ However, the underlying cause of POI remains unknown in 70 percent of cases. This paper focuses on women who are going through menopause at the typical age of 40+, as fertility issues for those with POI are very different than those for women following the more typical menopausal trajectory.  

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Table 1. Summarizes some of the key points regarding female reproductive phases

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How does menopause impact fertility? 

During the transition from the reproductive phase to menopause, there are several hormonal changes that occur.  

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Table 2. Summarizes the impact of different stages of menopause on fertility-related hormones

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FSH is the hormone required to stimulate the growth and maturation of ovarian follicles prior to ovulation. As the total number of oocytes in the ovaries decreases with age, more FSH must be secreted to stimulate the development of a follicle. Therefore, FSH rises as menopause approaches.  

Inhibin B is predominantly produced by antral follicles, which develop with FSH stimulation. It is therefore a marker of ovarian reserve as the declining number of follicles seen throughout perimenopause secrete less inhibin B.  

AMH is produced as primordial follicles in the ovaries develop into primary follicles during the oocyte maturation process. It is considered a marker of ovarian reserve that decreases over time and will generally be low (<1 ng/mL) in the menopausal transition as the number of follicles decreases.^ix Several studies have shown that AMH levels are a good predictor of time to menopause, illustrating the association of declining AMH levels and approaching natural menopause.^x,xi

In the premenopausal stage, estrogen may fluctuate, but does not begin to decrease significantly until perimenopause.^xii During early and late perimenopause, AMH and inhibin B levels, along with the antral follicle count, remain low and continue to decline.  The FSH level may start to increase if it has not already.^xiii Once an individual reaches late perimenopause, FSH levels may exceed greater than 25 IU/L, indicating significantly decreased ovarian reserve.^xiv  

Once an individual is postmenopausal, FSH is stably elevated and no longer rising, indicating infertility or an extremely low probability of pregnancy with one’s own eggs. Similarly, AMH levels are very low to undetectable, inhibin B levels are very low, and the antral follicle count is very low.^xv Additionally, estradiol continues to decrease for around two years after the final menstrual period, then stabilizes.^xvi

Pregnancy during menopause 

After menopause, conception at home is typically no longer possible. Pregnancy without assistance requires the release of an ovum through ovulation, and therefore cannot occur unless an individual is having ovulatory menstrual cycles. Cycles are typically still ovulatory during the early menopausal transition (early perimenopause). Menstrual cycles begin to become anovulatory (without ovulation) more frequently during the late menopausal transition (late perimenopause). While most cycles are anovulatory nearing the final menstrual period, when ovulatory cycles do occur, they are still hormonally normal.^xvii

As a result, there is still a chance of conception in the perimenopausal transition, leading up to the final menstrual period. After the final menstrual period, it is typically not possible to conceive without assisted reproductive technology.^xviii

There are extremely rare cases where ovulation has been known to occur in the postmenopausal period (after 12 months of amenorrhea). For example, a case published in 2007 detailed a woman who ovulated three years after menopause.^xix

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Chances of getting—and staying—pregnant during menopause 

As age increases, the percentage of in vitro fertilization (IVF) embryo transfers that result in live births decreases for women using their own eggs with live birth rates in the single digits per IVF cycle as patients approach 45 years of age (Figure 1). In contrast, IVF live birth rates decrease only slightly if individuals over 45 use donor eggs, meaning that the age-related decline is primarily due to egg quality. For example, in those aged 45 years or older, around 8.7 percent of embryo transfers completed in the US in 2019 resulted in a live birth when a patient’s own eggs were used.^xx However, nearly 40 percent of transfers using donor eggs in those greater than 45 resulted in a live birth. As the average age of menopause is 51 years, these statistics likely included women who were post-menopausal. Of note, this data only included embryo transfers completed in 2019, and there is likely to be year to year variability.^xxi

Figure 1. Percentage of embryo transfers that results in live births by patient age and egg source at US fertility clinics in 2019. The data is collected by Society for Assisted Reproductive Technology (SART) and published by the Centers for Disease Control (CDC). ^xxii

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When looking at the success rates among patients over 45 years of age, these rates (graph above) reported by SART only consider per transfer success rates. When looking at the odds of live births per cycle start (i.e., total number of females that started a cycle), this number will be considerably lower; this is because many females will have cancelled egg retrievals due to inadequate response to stimulation or may have eggs retrieved that do not lead to embryos that can be transferred.  

One retrospective study conducted at an IVF clinic that focuses on women of advance maternal age found that chances of live birth for women aged 43-51 years using their own eggs was less than 2 percent.^xxiii  

Another study, by Gunnala et al (2017), looked at women undergoing IVF with their own eggs. They found that for 45-year-old women, the live birth rate was only 4.4 percent per embryo transfer;^xxiv which will be even lower per cycle start since not all IVF cycles lead to embryo transfers.

Intrauterine insemination (IUI) is very unlikely to be successful for achieving pregnancy in perimenopause and menopause. A retrospective cohort study by Ruiter-Ligeti et al (2020) analyzed 325 IUI cycles for women over age 43 (range 43-47 years old). They found that of these cycles, only 5 (1.5 percent) resulted in pregnancy, and only 1 (0.3 percent) resulted in a live birth. The pregnancy rate did not differ with donor sperm vs. the partner’s own sperm^xxv

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Fertility treatments for menopausal women 

While the chance of conceiving a pregnancy without fertility treatment is low as menopause approaches, there are fortunately multiple family building options that remain available. Some options include adoption, surrogacy, or IVF with or without the use of donor eggs.

Because the onset of menopause indicates ovarian aging and diminished ovarian reserve, the best chance of achieving pregnancy requires the use of donor oocytes.^xxvi IVF with donor oocytes can be highly effective, even in postmenopausal women. A study by Paulson et al (2002) analyzed 77 women with a mean age of 52.8 who underwent IVF with donor oocytes. They found that there was a very high total pregnancy rate of 45.5 percent, with a live birth rate of 37.2 percent.^xxvii

Another study by Borini et al (1995) studied IVF with donor oocytes in postmenopausal women between the ages of 50-62 years old. These cycles were completed with hormone replacement therapy. They found that 18 of the 34 postmenopausal women were able to achieve pregnancy with donor oocytes, leading to an overall pregnancy rate of 52.9 percent. The pregnancy rate per embryo transfer was 32.7 percent, as some women underwent multiple transfers to achieve pregnancy.^xxviii

According to ASRM guidelines published in 2013, due to the high-risk nature of pregnancy, treatment to achieve a pregnancy is generally not recommended in women over 55 years old.^xxix This includes donor egg cycles.^xxx The upper age limit for IVF with donor eggs/embryos is variable by country and by clinic and some countries do not permit donor cycles in women over 45 years. In European countries, the maximum female age for assisted reproductive technology (ART) ranges from 45-51 years old with approximately 34 out of 43 European countries having age limits for ART.^xxxi Further, there are also sometimes age limits for those using government-funded IVF cycles. For example, in certain regions in Canada, one must be under the age of 43 to be eligible for a government-funded cycle of IVF.^xxxii

For assisted reproduction to be successful in postmenopausal women, hormone replacement with estrogen and progesterone is required for the first couple months after pregnancy is achieved. At this time, the placenta should be able to effectively produce the hormones required to sustain the pregnancy.^xxxiii

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Menopause and pregnancy: Staying healthy 

There is evidence to suggest that the uterus and endometrium are still functional in women who are postmenopausal, and pregnancy can still be achieved despite the onset of menopause.^xxxiv However, postmenopausal women must take extra precautions throughout their pregnancy as both mother and baby may be at higher risk for complications due to other factors associated with menopause. Additional testing is recommended for women of advanced maternal age who intend to achieve pregnancy via donor eggs or embryos.^xxxv Further, women over age 50 planning to undergo fertility treatments should be vaccinated against the herpes zoster virus, which causes shingles.^xxxvi

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Risks to baby 

There is always some degree of risk with any pregnancy, and while women of advanced maternal age can have healthy live births without complication, there are more potential risks with increasing age. For example, a retrospective analysis by Rendtorff et al (2017) compared pregnancy outcomes of 186 women over 45 years old to a group of 29-year-old women. They found that there was an increased risk of preterm deliveries (28 percent) in the advanced maternal age group compared to in the 29-year-old group (11 percent).^xxxvii

A study by Bouzaglou et al (2020) compared a group of 1 982 women who delivered at the age of 40 years or older to a group of 1 982 women who delivered between ages 25-35 years. They found that there was a significantly higher risk of fetal death in utero, intrauterine growth restriction, and prematurity in the group over 40 years old.^xxxviii

In general, the risk of chromosomal abnormalities increases as maternal age increases. However, utilizing donor eggs reduces this risk, as the oocyte age is related to the donor’s age at donation, rather than to the gestating mother’s age.^xxxix

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Risks to mother 

Pregnancy is associated with inherent risks to the mother independent of maternal age, because the changes that the body undergoes puts an increased stress on the body’s organ systems. As a woman approaches menopause, these organ systems naturally age, and women are more likely to develop chronic diseases such as hypertension or diabetes. Therefore, the stress of pregnancy on the body becomes increasingly significant with increasing maternal age, and the inherent risks of pregnancy are augmented. Being older than 45 years old has been shown to be an independent risk factor for gestational diabetes, and hypertensive disorders of pregnancy (including preeclampsia/eclampsia).^xl

In addition, complications related to pregnancy in women over 45 years old have been shown to have an increased mortality rate. In one study, patients over 45 years old accounted for only 0.19 percent of all pregnancies in the study, but the mortality rate was increased in this age group and accounted for 2 percent of the deaths and cardiac events identified in the study.^xli Though, it is important to also note that these are risk factors, and many women above 45 years old will have successful pregnancies (i.e., with donor eggs, donor embryos, previously frozen eggs, and more rarely with own eggs). The same retrospective analysis by Rendtorff et al (2017), mentioned above also found that there was a higher incidence of preeclampsia in the over 45 years of age group. They found that 7.5 percent of women aged 45 or older had preeclampsia, compared to 2.7 percent in the 29-year-old cohort.^xlii

Older individuals are also more likely to undergo caesarean section delivery. An older study from Paulson et al (2002) looked at 77 postmenopausal woman who did not have any known chronic conditions and who underwent IVF with donor eggs. They found that the rate of caesarean birth is higher in women over 50 years old. Out of their 77 patients, 68 percent who delivered singletons and 100 percent who delivered multiples underwent caesarean delivery.^xliii The normal rate of caesarean birth in 2002 was approximately 24 percent; therefore, this represents a significantly elevated rate.^xliv

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Conclusion

Menopause marks the end of fertility in women, a fact that can necessitate difficult decision-making for those who are still hoping to achieve a pregnancy and live birth. As assisted reproductive technology has continued to develop, the potential for achieving pregnancy at an advanced maternal age has grown, though there remain significant hurdles.  

Given the constraints that menopause can bring, it is critical for women at any age to understand the different stages of menopause and the commensurate impacts on fertility. Not only are there issues related to becoming pregnant, but there is also a chance for higher pregnancy and post-pregnancy complications for women who are experiencing some form of menopause. Any woman of advanced maternal age who is thinking of becoming pregnant or pursuing fertility treatments should discuss with her physician or reproductive immunologist exactly what this might entail and the risk factors involved.