Hype, Hormones and Hypermobility

Do you struggle to understand the complex interplay of hormones and hypermobility? Yep... me too.

Meet Cortney Gensemer, Ph.D., a postdoctoral scholar in the Norris Lab at MUSC. She and her colleagues are at the forefront of Ehlers-Danlos Syndromes (EDS) research. Cortney is a fellow Zebra who understands from first-hand experience how troubling an EDS diagnosis can be. Her disease pushes her to work hard because she aspires to find an answer for all of us.

How does she manage it all? Cortney says, "I'm going to be in awful chronic pain whether I'm sitting on the couch or in the lab so I may as well study my disease."

Read on to learn the findings of Dr. Gensemer's research on hypermobility and hormones.

-Linda Bluestein, M.D.

Hype, Hormones and Hypermobility

Have you heard of a relationship between the Ehlers-Danlos syndromes or hypermobility and hormones? Or that patients could be at increased risk of hormonal abnormalities?

So, all we need to do is just normalize those levels, eh?

Not so fast there, Zebra sista! As usual, the picture is just a wee bit more complicated than that.

First, let’s take a peek at the research.

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Key Points:

• The effect of hormones can depend on the tissue being affected (muscle vs ligament vs bone) and is not as simple as certain hormones being “good” or “bad”

• Hormones appear to have different influences on maintenance and after injury/in healing

• Hormones have been studied in athletes and cell culture models but data on people with EDS is really limited to surveys

• Underlying hormonal imbalances in patients should be considered (focus on individuals, not blanket statements for all EDS patients)

• Endogenous and exogenous hormones could have different effects, this hasn't been studied.

• In the context of EDS, when we don’t know the exact mutations at play for all patients, hormonal effects can be drastically different. (some genes can be upregulated or downregulated by hormones!)

• We really need more research to understand exactly how hormones impact EDS patients!

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Hormonal influence on tissue laxity, injury, healing in a “healthy” population:

Estrogen:

Estrogen plays a role in puberty, ovulation, pregnancy, and menopause in people assigned female at birth (AFAB) people. In AMAB (assigned male at birth) people, estrogen is also present and plays a role in reproductive health. Outside of reproductive health, estrogen can impact cholesterol, blood sugar, bone and muscle mass, skin health, collagen production, and cognitive function.

More research is needed related to estrogen and tendon/ligament health and laxity but clinical and animal studies so far have shown:

• Risk of suffering an ACL (anterior cruciate ligament - a ligament in the knee) disruption is significantly greater during the preovulatory/follicular phase of the menstrual cycle compared with the postovulatory phase (1)

• Higher risk of ACL tear in the ovulatory phase (2,3)

• Smaller collagen fibrils in people receiving ERT (estrogen replacement therapy) and lower young’s modulus (more elastic tendons) BUT they also had higher collagen turnover (important for injuries/homeostasis) (4)

• Estrogen decreases ACL strength in rabbits (5)

• Estrogen treatment of engineered ligaments leads to laxity (6)

• Estrogen is needed for injury recovery and in that case, it appears to enhance collagen synthesis (7)

• Estrogen replacement therapy may be beneficial for post-menopausal women in preventing tendinopathies (8)

• Increased knee laxity in women at higher estrogen levels (9)

Progesterone:

Progesterone is a hormone produced in ovaries after ovulation and is often referred to as the 'pregnancy hormone'. Progesterone is high during pregnancy and drops at menopause. In AMAB individuals, progesterone is produced by the adrenal glands and facilitates spermiogenesis and androgen synthesis. Baseline levels are comparable to AFAB people prior to ovulation. Aside from reproductive purposes, progesterone has also been studied for it's role in neurological disorders, osteoporosis, benign prostate hyperplasia, the nervous system and myelin regulation, and musculoskeletal regulation.

There is very little research on the relationship between progesterone and tendon or ligament health and laxity studies so far have shown:

• Knee laxity increases with high progesterone and high estrogen in rats (10)

• Increased knee laxity in women at higher progesterone levels (9)

Testosterone:

Testosterone is considered the male sex hormone in AMAB people and regulates sexual development including male hair patterns and vocal changes. Testosterone also has a lot of important roles outside of reproduction including regulating muscle mass, fat distribution, and red blood cell production.

In the context of musculoskeletal syndromes, research is limited but has shown:

• Testosterone can cause tendon stiffness (10)

• Having high testosterone and high estrogen can contribute to ACL tear risk in males (11)

• Testosterone reduced knee range of motion in rats (12)

Hormonal Contraceptives in a “healthy” population:

Some studies have been conducted to understand how hormonal contraception might affect the risk of tendon or ligament injuries.

• A protective association between oral contraceptive use and the likelihood of ACL injury has been seen but should not be used as a prophylactic measure before additional clinical studies have further clarified the biological and causal association between OC use and the likelihood of sustaining operatively treated ACL injury. (13)

• Possible lower risk of ACL injury with oral contraceptives (14)

Clinical Observations in EDS patients:

There have only been a few studies conducted on hormones in EDS patients, which are limited to surveys that don't include measuring patient hormone levels.

• An increase in dislocations and symptoms at puberty, during pregnancy, postpartum, and during the perimenstrual period have been reported (15,16)

• Some reported improvement after menopause (16)

• Anecdotal reports of female to male transgender individuals feeling improvement of symptoms with testosterone. This has not been studied or published, and we need to be careful that patients don’t read this as “testosterone could be a treatment” – I get this question a lot.

Summary:

The current understanding of how hormones regulate ligament and tendon strength and healing is limited. Hormones such as testosterone, estrogen, and progesterone have been shown to influence tendon, ligament, muscle, and bone properties, but the specifics of how it happens in humans, and how the menstrual cycle could play a role is unclear.

The combinations of hormones may have a synergistic or antagonistic effect that we don't yet understand. It's also possible that naturally produced hormones could have a different effect than synthetic or supplemental hormones.

Because this research is still in its infancy, it is hard to draw conclusions about how hormones play a role in connective tissue diseases like EDS. We need a better understanding of the genetics and biology involved in EDS, to know how hormones could fit into those pathways and contribute to the severity or progression of symptoms.

Blanket statements for EDS patients about hormonal contraceptives should not be made at this time.

It is important that physicians continue to treat each EDS patient as an individual. After all, no two zebras have the same stripes!

About the Author

Cortney is a postdoctoral scholar in the Norris Lab at the Medical University of South Carolina. Cortney graduated from West Chester University of Pennsylvania in 2018 with a bachelor's in Pharmaceutical Product Development and a Ph.D. in biomedical sciences from MUSC. Her current research is focused on the genetic and molecular mechanisms of hypermobile Ehlers Danlos Syndrome (hEDS). She hopes to advance diagnostic tools to accurately diagnose hEDS and develop therapies to treat the disease. Beyond basic science, Cortney aims to transform clinical care for hEDS patients in the future through the development of a multidisciplinary EDS clinic. She is also a member of the alliance for disability advocacy at MUSC and is an outspoken advocate for disabilities in STEM.

For more information about Cortney's story, click here.

ID: A picture of Cortney Gensemer. She's seen standing in a white dress with polka dots.

Resources

1. https://pubmed.ncbi.nlm.nih.gov/16436538/

2. https://pubmed.ncbi.nlm.nih.gov/11912085/

3. https://pubmed.ncbi.nlm.nih.gov/17909824/

4. https://journals.physiology.org/doi/full/10.1152/japplphysiol.90935.2008?rfr_dat=cr_pub++0pubmed&url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org

5. https://onlinelibrary.wiley.com/doi/10.1002/jor.1100170316

6. https://pubmed.ncbi.nlm.nih.gov/25979936/

7. https://pubmed.ncbi.nlm.nih.gov/27535256/

8. https://www.ncbi.nlm.nih.gov/pubmed/17394473

9. https://pubmed.ncbi.nlm.nih.gov/16558557/

10. https://pubmed.ncbi.nlm.nih.gov/26447688/

11. https://pubmed.ncbi.nlm.nih.gov/27535256/

12. https://pubmed.ncbi.nlm.nih.gov/25160472/

13. https://pubmed.ncbi.nlm.nih.gov/24642882/

14. https://pubmed.ncbi.nlm.nih.gov/25428957/

15. https://pubmed.ncbi.nlm.nih.gov/26540261/

16. https://journals.lww.com/greenjournal/Abstract/2014/03000/Obstetric_and_Gynecologic_Challenges_in_Women_With.5.aspx

17. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5020453/