Anti-Mullerian hormone may contribute to infertility in polycystic ovary syndrome

Date:
March 9, 2022
Source:
Weill Cornell Medicine
Summary:
High levels of anti-Mullerian hormone (AMH) have traditionally
been thought of as merely a passive byproduct of polycystic ovary
syndrome (PCOS), but a new preclinical study suggests that the
hormone plays an active role in the disorder and may contribute
to problems with ovulation and fertility.



FULL STORY ==========================================================================
High levels of anti-Mullerian hormone (AMH) have traditionally been
thought of as merely a passive byproduct of polycystic ovary syndrome
(PCOS), but a new preclinical study by Weill Cornell Medicine researchers suggests that the hormone plays an active role in the disorder and may contribute to problems with ovulation and fertility.


==========================================================================
In the study, published March 9 in Science Advances, the investigators discovered that AMH may cause follicles, the multicellular, fluid-filled
sacs that contain developing eggs in the ovary, to mature too quickly.

"AMH is routinely measured in the clinic to give an indication of how
many follicles a woman has growing in her ovaries, and this value is
often high in women with PCOS. But no one has ever determined whether
a high level of AMH, by itself, can have a negative influence," said
senior author Dr. Daylon James, assistant professor of stem cell biology
in obstetrics and gynecology and in reproductive medicine at Weill
Cornell Medicine. "A better understanding of the root causes of PCOS
is critical to mitigating the condition's many health consequences."
Developing eggs, called oocytes, are produced in the ovaries within
follicles, which support their growth. As the follicle grows, the egg
that resides within it gradually matures, and in a normal reproductive
cycle, that follicle ultimately undergoes ovulation to release an egg
capable of being fertilized.

However, in patients with PCOS, a hormonal disorder that impacts up to
10 percent of women, the ovaries contain numerous smaller follicles that produce AMH, but fail to progress to later stages and ovulate.

While fertility treatments can help with conception, women with
PCOS contend with a variety of other symptoms, said Dr. James. For
example, PCOS is often accompanied by hyperandrogenism, or high
levels of hormones such as testosterone that are collectively called
androgens. An overabundance of these hormones can cause an array of
secondary complications, including unwanted growth of body and facial
hair. Women with PCOS can also be prone to diabetes and metabolic disease
and are more susceptible to endometrial cancer.

Dr. James and his research team hypothesized that AMH is directly
contributing to at least some of the constellation of symptoms associated
with the disorder.

To isolate the effects of AMH, the researchers utilized a xenograft
system in which ovarian tissue from human organ donors is engrafted onto
the flank of immunocompromised mice. One group of mice was transplanted
along with cells that continuously supplied AMH directly to the grafted
tissue, and the other group of mice was transplanted with control cells
without AMH.



========================================================================== "What we have here is a unique opportunity to take tissue from the same
human donors and allocate it to both experimental groups -- the group with
AMH and the group without AMH," said first author Dr. Limor Man, assistant professor of research in obstetrics and gynecology and in reproductive medicine, and the Hung-Ching Liu Research Scholar in obstetrics and
gynecology. "This is actually the best control you can hope for in these
types of experiments." By contrast, when researchers compare patients
with PCOS to those without the disorder in clinical studies, a variety of influencing factors, such as genetic predispositions and varying levels
of different reproductive hormones, must be considered, she said.

The researchers discovered that the ovarian tissue exposed to high
AMH contained follicles that showed characteristics evident at a much
later stage of development. Specifically, the follicles were undergoing luteinization, a process that occurs immediately leading up to ovulation, before any of the oocytes were ready.

"AMH is causing the usually coordinated growth process between a follicle
and its resident oocyte to fall out of synch," said Dr. James, who
is also the Queenie Victorina Neri Research Scholar in obstetrics and gynecology and assistant professor of genetic medicine at Weill Cornell Medicine. "It is like baking with the oven too hot," he said. "The
outside, or the cellular component of the follicle, is overcooked,
while the inside, or oocyte, is not done." "Based on ultrasounds showing persistent presence of multiple small follicles in the ovary, infertility
in women with PCOS has been attributed to stalled growth and resultant
failure in egg maturation," Dr. Man said. "But recent data indicates that "stalled" follicles in these patients are actually a steady stream of
newly growing, but abortive follicles." This new study puts forth the
revised interpretation that the persistent array of small follicles in
PCOS ovaries represent a continuous succession of follicles undergoing
rushed maturation and failure to ovulate.

Considering the broad prevalence of PCOS, the factors that contribute to
its emergence remain poorly understood. Although treatments exist for individual facets of disease, the condition rarely recedes until women
reach the end of their reproductive lifespan. The identification of a
novel AMH-driven mechanism for failed follicle development suggests
that it can contribute to this, and perhaps other, facets of PCOS
disease symptoms.

"With further research, we hope to develop drug treatments that target
the effects of AMH, which could help restore the menstrual cycle in women
with PCOS and manage other symptoms of the condition," Dr. James said.


========================================================================== Story Source: Materials provided by Weill_Cornell_Medicine. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Limor Man, Nicole Lustgarten Guahmich, Eleni Kallinos, Barbara
Caiazza,
Monica Khan, Zong-Ying Liu, Ritaben Patel, Carmen Torres,
David Pepin, He S. Yang, Richard Bodine, Nikica Zaninovic, Glenn
Schattman, Zev Rosenwaks, Daylon James. Chronic superphysiologic
AMH promotes premature luteinization of antral follicles in
human ovarian xenografts. Science Advances, 2022; 8 (10) DOI:
10.1126/sciadv.abi7315 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/03/220309140828.htm

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