Testosterone, EDS, and POTS, Oh My?

Does Testosterone Hold a Clue to Ehlers Danlos Syndrome Symptoms?

I recently attended a major science conference—the Ehlers Danlos Society International Scientific Symposium—and a surprising piece of unpublished research caught my attention, especially as I specialize in menopause. It was about how people with hypermobile Ehlers-Danlos Syndrome (hEDS) seem to have unusual androgen pathways, which help create hormones like testosterone.

Just days before, a patient with dysautonomia (a nerve problem that affects body functions) mentioned her own specialist had noticed that many of his patients have low testosterone. Putting these two pieces of information together made me wonder: Could there be a connection between testosterone and the three main features of hEDS (what we call the EDS triad: loose joints/hypermobility, mast cell activation, and nervous system dysfunction)?

But is there any solid data to back up this hunch?

The Hormone Puzzle

Let's start with what we already know. Hypermobile EDS is much more common in women (estimated at 90%) than in men (10%) [1,2].

It’s also common for hEDS symptoms to start right around the time of puberty. In one study of 286 French women with hEDS, the average age when symptoms began was 12.5 years—the typical age for puberty [3]. While this could be a coincidence, it strongly suggests a link. It could mean that either estrogen and progesterone (female-dominant hormones) make things worse, or that androgens like testosterone (male-dominant hormones) offer some protection.

This idea is supported by the fact that women with hEDS report much worse symptoms overall—including problems with muscles, bones, nerves, and digestion—compared to men [4,5].

A similar pattern is seen in POTS (Postural Orthostatic Tachycardia Syndrome), a common condition related to hEDS. Large studies consistently show that about 80–90% of POTS patients are female, and it usually starts one to two years after puberty [6,7]. And similarly, MCAS (Mast Cell Activation Syndrome) is most commonly reported in women [8].

How Hormones Impact Symptoms

Changes in hormone levels—like those during puberty, pregnancy, after childbirth, and even before a period—are known to increase the frequency and severity of joint dislocations and other symptoms for people with hEDS. Many women report that their pain, joint instability, and gynecologic issues (like heavy or painful periods) get worse during these times of hormonal flux [3,9-10].

Estrogen and relaxin (a hormone involved in pregnancy) are known to loosen the body's ligaments by interfering with collagen, which is the "glue" that holds our tissues together [11-12]. This could certainly contribute to unstable joints and a higher risk of dislocation.

Testosterone, on the other hand, is generally linked to increased stiffness in tendons, and more collagen [12]. In theory, testosterone might reduce joint looseness, but we don't have direct proof of a protective effect in hEDS.

Tissue laxity (looseness) from higher estrogen and lower testosterone is also thought to contribute to POTS. Loose blood vessels are more flexible, which causes blood to pool in the legs when a person stands up. This pooling reduces the amount of blood returning to the heart and brain, triggering a compensatory fast heartbeat (tachycardia) and worsening symptoms like dizziness and palpitations [7,13].

What do we know about hormones and mast cells? Interestingly, mast cells have hormone receptors directly attached to them. Estrogen and progesterone typically promote activation and mediator release from mast cells, while testosterone can reduce the activation of mast cells and severity of disease [14,15]. Much like hEDS and POTS patients, many women report changing MCAS symptoms throughout the menstrual cycle [14].

So... Should We Just Add Testosterone?

This is where things get complicated.

There are currently no published studies (that I am aware of) investigating whether testosterone replacement therapy in women improves hEDS, POTS, or MCAS symptoms.

While clinicians hear informal stories that gender-affirming care for our transgender patients can impact EDS symptoms, no official clinical trials or large studies have evaluated these changes. Until we have that formal data, we have to look at anecdotal reports. This Reddit forum, for instance, has many posts from trans women and trans men with hEDS/POTS/MCAS—often called "zebras" in the community—reporting symptom changes with hormone therapy. Trans men frequently report improvements in muscle development, joint stability, fatigue, and pain. Others note minimal changes.

It’s also important to remember that when a cisgender woman is given testosterone replacement, the dose is usually only about 10% of a typical male dose, so any true effects may be less noticeable in this population.

While the connections between hormones, loose joints, POTS, and mast cell activation are compelling, we have to recognize the logical gap: We're seeing correlations (female dominance, puberty onset), and hearing anecdotes about low testosterone, but we don't yet have large studies confirming that women with hEDS have a measurable testosterone deficiency. This is the difference between a great hypothesis and proven medicine. That said, if someone who was assigned female at birth comes to me with hEDS, POTS, or MCAS and confirmed low testosterone, I'm certainly open to exploring this as what could be a brief and likely safe experiment. I may even see a PhD topic in my future...

We'd love to hear from you! Have you ever tried testosterone for symptom management? What was your experience?

Citations:

1. Clinical Characteristics of Patients With Hypermobile Type Ehlers-Danlos Syndrome (hEDS) and Generalized Hypermobility Spectrum Disorders (G-Hsd): An Online Survey. Teran-Wodzinski P, Kumar A. Rheumatology International. 2023;43(10):1935-1945. doi:10.1007/s00296-023-05378-3.

2. Subjective Health Complaints in Individuals With Ehlers-Danlos Syndrome: A Questionnaire Study.

   Maeland S, Assmus J, Berglund B.

   International Journal of Nursing Studies. 2011;48(6):720-4. doi:10.1016/j.ijnurstu.2010.10.007.

3. Gynecologic Symptoms and the Influence on Reproductive Life in 386 Women With Hypermobility Type Ehlers-Danlos Syndrome: A Cohort Study.

   Hugon-Rodin J, Lebègue G, Becourt S, Hamonet C, Gompel A. Orphanet Journal of Rare Diseases. 2016;11(1):124. doi:10.1186/s13023-016-0511-2.

4. Subjective Health Complaints in Individuals With Ehlers-Danlos Syndrome: A Questionnaire Study.

   Maeland S, Assmus J, Berglund B. International Journal of Nursing Studies. 2011;48(6):720-4. doi:10.1016/j.ijnurstu.2010.10.007.

5. Hypermobile Ehlers-Danlos Syndromes: Complex Phenotypes, Challenging Diagnoses, and Poorly Understood Causes.

   Gensemer C, Burks R, Kautz S, et al. Developmental Dynamics : An Official Publication of the American Association of Anatomists. 2021;250(3):318-344. doi:10.1002/dvdy.220.

6. Postural Orthostatic Tachycardia Syndrome: Clinical Presentation, Aetiology and Management.

   Fedorowski A.

   Journal of Internal Medicine. 2019;285(4):352-366. doi:10.1111/joim.12852.

7. Gynecologic Considerations for Adolescents and Young Women With Cardiac Conditions.

   American College of Obstetricians and Gynecologists’ Committee on Gynecologic Practice, Judith Simms-Cendan

   American College of Obstetricians and Gynecologists (2020)

8. Characterization of Mast Cell Activation Syndrome.

   Afrin LB, Self S, Menk J, Lazarchick J.

   The American Journal of the Medical Sciences. 2017;353(3):207-215. doi:10.1016/j.amjms.2016.12.013.

9. Obstetric and Gynecologic Challenges in Women With Ehlers-Danlos Syndrome.

   Hurst BS, Lange SS, Kullstam SM, et al.

   Obstetrics and Gynecology. 2014;123(3):506-513. doi:10.1097/AOG.0000000000000123.

10. Gynecologic and Obstetric Implications of the Joint Hypermobility Syndrome (a.k.a. Ehlers-Danlos Syndrome Hypermobility Type) in 82 Italian Patients.

    Castori M, Morlino S, Dordoni C, et al.

    American Journal of Medical Genetics. Part A. 2012;158A(9):2176-82. doi:10.1002/ajmg.a.35506.

11. Characterization of the Relationship Between Joint Laxity and Maternal Hormones in Pregnancy.

    Marnach ML, Ramin KD, Ramsey PS, et al.

    Obstetrics and Gynecology. 2003;101(2):331-5. doi:10.1016/s0029-7844(02)02447-x.

12. Sex Hormones and Tendon.

    Hansen M, Kjaer M. Advances in Experimental Medicine and Biology. 2016;920:139-49. doi:10.1007/978-3-319-33943-6_13.

13. Women, Orthostatic Tolerance, and POTS: A Narrative Review.

    Fitzgibbon-Collins LK, Pereira TJ, Edgell H. Autonomic Neuroscience : Basic & Clinical. 2025;259:103284. doi:10.1016/j.autneu.2025.103284.

14. Role of Female Sex Hormones, Estradiol and Progesterone, in Mast Cell Behavior.

    Zierau O, Zenclussen AC, Jensen F.

    Frontiers in Immunology. 2012;3:169. doi:10.3389/fimmu.2012.00169.

15. Perinatal Androgens Organize Sex Differences in Mast Cells and Attenuate Anaphylaxis Severity Into Adulthood.

    Mackey E, Thelen KM, Bali V, et al.

    Proceedings of the National Academy of Sciences of the United States of America. 2020;117(38):23751-23761. doi:10.1073/pnas.1915075117.