The stages of menopause

Natural menopause does not happen instantly; it is a gradual transition that can occur over multiple years.  The entire process includes three stages:

• ‍Perimenopause: This stage can last several years prior to arriving at menopause.
• ‍Menopause: A single day 12 months after the last menstrual cycle.
• ‍Postmenopause: The rest of a female’s life after she reaches menopause.

Menopause is officially diagnosed when a female has not menstruated for one year. The median age at which an individual has her final menstrual period is 51.4 years.ⁱ Once menopause occurs, a female is said to be in the postmenopausal stage. Therefore, menopause and postmenopause are synonymous for the purposes of this article.ⁱⁱ

Surgical menopause

Menopause can 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 it causes an abrupt onset of menopausal symptoms, compared to the gradual progression of natural menopause.  

Premature ovarian insufficiency (POI)

When the loss of normal ovarian function due to diminished ovarian reserve occurs prior to the age of 40, it is considered premature ovarian insufficiency (POI). It is often colloquially referred to as premature or early menopause. Approximately 1 percent of females under the age of 40 and 0.1 percent of females 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 article focuses on females who are going through menopause at the typical age of 40+, as fertility issues for individuals with POI are very different than issues for females following the more typical menopausal trajectory.

How does menopause impact fertility?

During the transition from the reproductive phase to menopause, there are several hormonal changes that occur, specifically related to follicle stimulating hormone (FSH), anti-Müllerian hormone (AMH), inhibin B, and estrogen.

Follicle stimulating hormone (FSH)

Follicle stimulating hormone (FSH) triggers the growth and maturation of ovarian follicles before ovulation. As the total number of oocytes in the ovaries decreases with age, more FSH must be secreted to stimulate follicle development. Therefore, FSH rises as menopause approaches.^ix

Once an individual reaches late perimenopause, FSH levels may exceed 25 IU/L, indicating significantly decreased ovarian reserve.^x By postmenopause, FSH is stably elevated and no longer rising, indicating infertility or an extremely low probability of pregnancy with one’s own eggs.^xi

Anti-Müllerian hormone (AMH)

After primordial follicles in the ovaries develop into more mature follicles, their cells will secrete AMH. It is considered a marker of ovarian reserve that decreases over time and will generally be low (less than 1 ng/mL) in the menopausal transition as the number of follicles decreases.^xii Several studies have shown that AMH levels are a good predictor of time to menopause, illustrating the association of declining AMH levels and the approach of natural menopause.^xiii,xiv After menopause is reached, AMH levels will be very low to undetectable.^xv

Inhibin B

Inhibin B is predominantly produced by antral follicles, which develop with FSH stimulation. As the number of growing follicles declines throughout perimenopause, less inhibin B is secreted, and the levels begin to lower. Therefore, inhibin B is a marker of ovarian reserve.

Estrogen

In the premenopausal stage, estrogen levels may fluctuate but do not begin to decrease significantly until perimenopause.^xvi Estrogen (specifically estradiol) will continue to decrease for around two years after the final menstrual cycle, then stabilize.^xvii

Pregnancy during menopause

After menopause, conception at home is typically no longer possible because pregnancy without assistance requires the release of an ovum through ovulation. Natural pregnancy cannot occur unless an individual is having ovulatory menstrual cycles. Here are the chances that cycles are ovulatory based on the stage of menopause:^xviii

• ‍Early perimenopause: Cycles are typically still ovulatory during the early menopausal transition.
• ‍Late perimenopause: Menstrual cycles begin to become anovulatory (without ovulation) more frequently during the late menopausal transition.
• ‍Nearing menopause: Most cycles are anovulatory nearing the final menstrual period. However, when ovulatory cycles do occur, they are still hormonally normal.^xix
• ^‍After the final menstrual period: In the year leading up to menopause and afterwards (postmenopause), there are no more menstrual periods. In almost all cases, that means ovulation has stopped.

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 (ART).^xx

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 female who ovulated three years after menopause.^xxi

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 females using their own eggs. Live birth rates are 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 females aged 45 years or older, around 8.7 percent of embryo transfers completed in the U.S. in 2019 resulted in a live birth when a patient’s own eggs were used.^xxiii However, nearly 40 percent of transfers using donor eggs in those older than 45 resulted in a live birth. As the average age of menopause is 51 years, these statistics likely included patients 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.^xxiv

When looking at the success rates among patients over 45 years of age, these rates reported by SART (graph above) 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; 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 individuals of advance maternal age found that chances of live birth for females aged 43 to 51 years using their own eggs was less than 2 percent.^xxv

Another study, by Gunnala et al (2017), looked at females undergoing IVF with their own eggs. They found that for 45-year-old females, the live birth rate was only 4.4 percent per embryo transfer.^xxvi The rate per cycle start would be even lower, 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 females over age 43 (range 43 to 47 years old). They found that of these cycles, only five (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 versus partner sperm.^xxvii

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 including adoption, surrogacy, or IVF with or without donor eggs.

Because the onset of menopause indicates ovarian aging and diminished ovarian reserve, the best chance of achieving pregnancy involves the use of donor oocytes (eggs).^xxviii IVF with donor oocytes can be highly effective, even in postmenopausal females. A study by Paulson et al (2002) analyzed 77 patients 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.^xxix

Another study by Borini et al (1995) studied IVF with donor oocytes in postmenopausal females between the ages of 50 and 62 years old. These cycles were completed with hormone therapy. They found that 18 of the 34 postmenopausal patients 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 individuals underwent multiple transfers to achieve pregnancy.^xxx

For assisted reproduction to be successful in postmenopausal females, hormone therapy 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.^xxxi

Age limits for fertility treatment

According to the American Society for Reproductive Medicine (ASRM) guidelines published in 2013, treatment to achieve a pregnancy is generally not recommended in females over 55 years old due to the high-risk nature of pregnancy.^xxxii These guidelines apply to donor egg cycles.^xxxiii

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 females over 45 years. In European countries, the maximum female age for assisted reproductive technology (ART) ranges from 45 to 51 years old with approximately 34 out of 43 European countries having age limits for ART.^xxxiv

There are also sometimes age limits for individuals 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.^xxxv

Menopause and pregnancy: Staying healthy

There is evidence to suggest that the uterus and endometrium are still functional in females who are postmenopausal, and pregnancy can still be achieved despite the onset of menopause.^xxxvi However, postmenopausal individuals 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 also recommended for patients of advanced maternal age who intend to achieve pregnancy via donor eggs or embryos.^xxxvii Further, people over age 50 planning to undergo fertility treatments should be vaccinated against the herpes zoster virus, which causes shingles.^xxxviii

Risks to baby

There is some degree of risk with any pregnancy. While females 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 females over 45 years old to a group of 29-year-old females. 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).^xxxix

A study by Bouzaglou et al (2020) compared a group of 1,982 females who delivered at the age of 40 years or older to a group of 1,982 females who delivered between ages 25 to 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.^xl

In general, the risk of chromosomal abnormalities increases with maternal age. 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.^xli

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 female approaches menopause, these organ systems naturally age. Therefore, the stress of pregnancy on the body becomes more significant with increasing maternal age.

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).^xlii A retrospective analysis by Rendtorff et al (2017) found that 7.5 percent of pregnant females aged 45 or older had preeclampsia, compared to 2.7 percent of 29-year-old females.^xliii

In addition, complications related to pregnancy in females 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.^xliv

Older individuals are also more likely to undergo caesarean section delivery. An older study from Paulson et al (2002) looked at 77 postmenopausal females 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 females over 50 years old. Out of their 77 patients, 68 percent who delivered singletons and 100 percent who delivered multiples underwent caesarean delivery.^xlv The normal rate of caesarean birth in 2002 was approximately 24 percent; therefore, 68 and 100 percent represent significantly elevated rates.^xlvi

Despite these risk factors, it is important to note that many females older than 45 years will have successful pregnancies with donor eggs, donor embryos, previously frozen eggs, and more rarely with their own eggs.

Conclusion

Menopause marks the end of fertility in females, a fact that can necessitate difficult decision-making for individuals who are still hoping to conceive. Given the constraints that menopause can bring, it is critical for females 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 naturally, but there is also a chance for higher pregnancy and post-pregnancy complications for females who are experiencing some form of menopause. Assisted reproductive technology has continued to develop, and the potential for achieving a healthy pregnancy at an advanced maternal age has grown, though there remain significant hurdles.

Any individual of advanced maternal age who is thinking of becoming pregnant or pursuing fertility treatments should have a conversation with her physician or reproductive immunologist. They can discuss exactly what the process towards pregnancy might entail, and the risk factors involved.