Fertility Preservation in Turner Syndrome

In this post, we’ll review some of the information shared during the webinar “Fertility Preservation in Girls with Turner Syndrome” hosted by the Turner Syndrome Foundation, featuring guest speaker Dr. Kutluk Oktay–an OB/GYN physician and professor at Yale University. We will discuss the process of fertility, how to test for infertility, and a special hormone involved.

Note: The information in this post is educational and should not replace medical advice from your medical professional(s). Always consult with them to be sure of any personal health concerns that you have.

Here are some key terms to help understand this article:

  • Anti-Müllerian hormone: a hormone secreted by the primordial follicles that can suggest fertility;
  • Antral follicle: fluid-filled, immature egg cells;
  • Antral follicle count: the count of fluid-filled follicles that can be seen via ultrasound medical imaging;
  • Estradiol (E2): a sub-type of the estrogen hormones that circulate in the body and promote the development of female sexual organs;
  • Follicle-stimulating hormone: a hormone that stimulates the growth and development of the ovaries;
  • Gonads: sexual organs; in females, this refers to the ovaries;
  • Luteinizing hormone: a hormone important in ovulation and development of female sexual organs;
  • Meiotic: type of cell that divides twice to form  cells containing half the amount of genetic information;
  • Menopause: the time at which a female stops menstruating (having their period);
  • Menstrual cycle: the process of ovulation and menstruation in females–also referred to as a period;
  • Mitotic: type of cell that divides into two identical daughter cells with the same amount of genetic information;
  • Oogonia: female germ cells that will eventually become eggs;
  • Ovulation: the process of releasing an egg from the ovary during the menstrual cycle;
  • Primordial follicle: the immature version of the egg cell that sits in the ovary until ovulation.

How does the process of fertility work?

After the conception of a daughter, mitotic cells, called oogonia, develop in their gut about 6 weeks into the pregnancy. These cells travel within the female fetus to reach their final destination, the gonads. In the gonads, they become meiotic cells and increase in numbers drastically. Surrounding the new home for these meiotic cells are supportive nurse cells that function to stop these cells from increasing in number. Thus, the primordial follicles are formed. The meiotic cells housed in the follicles will eventually become eggs. By 28 weeks of pregnancy, the female fetus contains the highest number of eggs that they will ever have–as many as 7 million eggs. From this peak, the number of eggs will begin to decline. At birth, the female baby can be born with as many as 1 million eggs.

After a female begins puberty, they ovulate once a month during their menstrual cycle. Subsequently, a female ovulates as many as 500 times throughout their life–losing an egg during each ovulation. However, this does not account for the 1 million eggs they started with. This means that ~99.9% of these eggs held for reserve are left unutilized. These extra eggs provide the opportunity for fertility treatments and emphasize the importance of earlier identification of TS.

Later in adulthood, there is an age-related decline in egg count that is normal for females–around the age of 37. For people with TS, the decline in egg count is dramatically accelerated. As a result, menopause occurs earlier for people with TS. There are a lot of variations in the rate at which egg count declines in people with TS based on the chromosome varieties. In some cases, egg count declines completely soon after birth. This speaks to the urgency of early testing for TS.

How to test for infertility and why it’s important

Since females do not begin to menstruate until early pre-teen years, many kids with TS won’t know if they’re infertile until it’s too late to do anything about it. Often, kids with TS  show cognitive differences that begin the diagnostic process for TS. At this point, some of those kids could have already lost all their eggs. If this happens, there isn’t much that can be done to preserve fertility in these individuals; egg donation or adoption may be options for building a family.

So how can we monitor children before puberty, to see if they have TS and egg reserve? There are some markers and tests that can be done. Reserve eggs are called primordial follicles that can sit around for decades with only one making ovulation per menstrual cycle. These primordial follicles develop and release a hormone called anti-Müllerian hormone (AMH). Physicians test for the level of this hormone in the blood to determine fertility. High amounts of AMH suggest a larger egg reserve. Low amounts of AMH suggest a decline in egg count.

Additionally, other structures in the ovary are suggestive of fertility. Antral follicles are fluid-filled, immature eggs that sit in the ovary. The fluid-filled nature of these cells enables physicians to use ultrasound imaging to count the number of antral follicles in a person’s ovaries. Physicians correlate these antral follicle counts (AFC) with age to determine a patient’s fertility. This can be challenging in babies, but still possible.

Lastly, other hormone levels to consider include:

  • Follicle-stimulating hormone (FSH): high levels are a sign of abnormally low egg reserve (infertility);
  • Estradiol (E2): not as helpful because levels of estrogen don’t begin to increase until puberty;
  • Inhibin-B: comes from late-stage follicles in the process of ovulation when puberty begins, so not as helpful for earlier diagnosis.

Let’s talk more about AMH

At birth, AMH levels are usually high within the first few months. However, those numbers begin to go down and stay low until about age 4 or 5, normally. Therefore, in this age range (birth – age 5), more workup may be required to determine fertility and egg reserve. After age 5, AMH levels in people with TS compared to values in the general population provide an assessment for fertility. These comparisons can help determine the relative age of the person with TS and how much time they have before reaching infertility.

In people with TS and absent puberty, AMH levels remain low or undetectable. If they have ovarian function, but then cessation of ovarian function later on, their levels may be a little higher than in the absent-puberty group. Lastly, if the person with TS has ongoing ovarian function with no disruption, then they will likely have the highest levels of AMH. Therefore, AMH levels in people with TS correlate with ovarian function.

When relating AMH levels to types of TS, people with classical TS–or TS where one X chromosome is globally missing from all cells in the body–exhibit low or undetectable levels of AMH. People with mixed karyotypes (e.g., ring chromosomes, structural abnormalities) tend to have mixed levels of AMH, but there’s more of a range between undetectable and low to mid-range. Finally, those with mosaic TS may have some of the highest relative levels of AMH. These people can still represent a range of AMH levels–i.e., some individuals with mosaic TS may have low amounts of AMH or high depending on the percentage of cells with a singular X chromosome. Early diagnosis is critical for all these variations of TS.

Takeaways for fertility in TS

Based on existing studies:

  • About 50% of people with mosaic TS (XX/XO) enter puberty;
  • 5-10% will have regular menstrual cycles;
  • Pregnancy is possible in 3-5% (primarily in people with 46XX mosaicism, distal Xp deletions, or Xq26-Xq27 locus preserved variations–consult with your physician to be sure which type of TS you are living with).

Dr. Kutluk Oktay, the webinar-presenting physician, worked with a team of physician colleagues to develop a free-access review and guideline article on fertility preservation in people with TS. These guidelines include a lot of the information mentioned here with more detail and references to specific studies. Feel free to bring this article to your physician to discuss options and fertility preservation. 

Written by Reyn Kenyon, TSF volunteer blog post writer and edited by Liz Donner, TSF volunteer editor.

To watch the webinar on fertility preservation in TS presented by Dr. Kutluk Oktay:


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