The Truth About Hormone Therapy | Office Hours

[01:05] Dr. Linda Bluestein: Welcome back, every bendy body, to the Bendy Bodies Podcast with your host and founder, Dr. Linda Bluestein, the Hypermobility MD. Today we are going to do another episode where you are my guest. I've had so many questions lately about hormones, and in particular the conversation I had with Dr. Casperson where we talked a lot about testosterone. So today we are going to focus on — air quotes — sex hormones: estrogen, progesterone, and testosterone, and how they pertain to menopause. We're going to talk about hormone replacement therapy. We're going to answer questions like how these hormones affect connective tissue. We're going to talk a little bit about the risks and the benefits of hormone replacement therapy. We are going to talk about the impacts of puberty and why people assigned female at birth tend to get worse and why people assigned male at birth may see improvements. We're also going to talk about gender-affirming hormone therapy and connective tissue disorders. And hormones and mast cells.
[02:00] Stick around until the very end so you don't miss any of our special hypermobility hacks. As always, this information is for educational purposes only and is not a substitute for personalized medical advice. Here we go.
[02:15] So as I mentioned, today's conversation is a result of the many, many questions I have received about hormone replacement therapy, testosterone, and the many, many hormones that we have in our bodies. This was a specific question that I received from a listener, so I'm going to start with reading this and trying to answer their question as best I can.
[02:35] "Almost the minute menopause hit fully, my joint pain and fatigue became exponentially worse. Three years later, I'm two weeks into prescription hormone replacement therapy because I asked my doctor if I could try it. Please discuss management of menopausal symptoms, if HRT is generally helpful, and if so, what time frame considerations are there? Why isn't this something PCPs would address without the patient having to come up with the idea? Two weeks of HRT and I already feel like my joints are better than they have been in years."
[03:06] So first of all, I'm glad that you're feeling better. I do want to point out that PCPs need to know about a lot of different things, as we discussed recently in an episode with Dr. Matthew Waddell, who is an internist. And so unfortunately, hormones being a very complex topic is something that's very nuanced, and a lot of PCPs actually don't tend to get super involved in hormone replacement therapy or conversations about these hormones. Whenever possible, it is actually better to get somebody with more expertise involved anyway.
[03:38] Like many of you, I suspect a strong relationship between my own symptoms and hormones. As I have mentioned during a previous episode, I am on low-dose hormone replacement therapy that was started shortly after menopause. When I lived in Wausau, Wisconsin, I had a great team. I had a breast surgeon, I had a specialist in menopause, and I felt like I had really, really great care. In fact, I'm really grateful to the OB-GYN who referred me on rather than treating me herself. OB-GYNs have to do a lot of things. They provide medical care to women that are pregnant. They deliver babies vaginally and by cesarean section. They do a lot of gynecologic surgeries and gynecologic medical care. So prescribing hormone replacement therapy is only a very small part of what they may or may not do.
[04:24] Unfortunately, here in Colorado, I have had a lot harder time getting really good quality coordinated specialty care for menopause.
[04:32] We're going to talk a little bit about estrogen, then progesterone, then testosterone. Then we'll talk about menopause. Then we'll talk about menarche, which is the onset of menstrual cycles. Then we'll talk about gender-affirming hormone therapy. And lastly, we'll talk about mast cell activation syndrome and how hormones are relevant there.
[04:49] I highly recommend that you listen to episode 131, which was the interview with urologist Dr. Kelly Casperson, and episode 130, which was an interview with Dr. Irwin Goldstein and his wife Sue Goldstein. As I mentioned earlier, episode 133 was an interview with Dr. Waddell, who is an internist, and we talked a little bit about this topic.
[05:08] Also, I want to point out that I'm not aware of any research specifically on hormone replacement therapy in people with EDS and HSD. So the studies that I'm going to mention are regarding hormones but not specifically in that population. Hormone replacement therapy can definitely alleviate some symptoms related to joint hypermobility, but the effectiveness can vary. There's, of course, a lot of anecdotal evidence, but also there are a lot of studies that we can look at for the effects of hormones on connective tissue.
[05:37] So first of all, what are "sex hormones"? That includes testosterone, estrogen, and progesterone. And I put that in air quotes because, as Dr. Kelly Casperson says, we really should consider these brain hormones. They play vital roles in brain function, sexual development, reproduction, and overall health. Testosterone is the primary androgen, and it's crucial for male sexual development, sperm production, muscle growth, bone density, and red cell production. But it's also extremely important for brain and tissue health in females. Estrogen, which is predominantly produced in females, regulates the menstrual cycle, supports bone density, and contributes to cardiovascular and neural health. Progesterone, which is primarily involved in female reproductive health, stabilizes menstrual cycles and prepares the body for pregnancy, but it also influences mood, immune function, and sleep. Though these hormones are present in both sexes at varying levels, especially at different times of life, together they regulate puberty, fertility, secondary sexual characteristics, and other essential physiologic processes.
[06:40] So first, let's talk about estrogen. Estrogen plays a complex role in connective tissue health. It influences collagen production, tissue elasticity, and structural integrity. It promotes collagen synthesis and incorporation into tendons, ligaments, and other connective tissues, which can improve tissue repair and resilience. During menopause, estrogen levels decline, and this is associated with reduced collagen synthesis and connective tissue degradation, leading to decreased elasticity and increased injury risk. Replacement therapy has been shown to partially reverse these effects by preserving collagen content and improving tissue turnover.
[07:16] The effects of estrogen vary depending on factors like hormone levels, age, and tissue type. Estrogen has been shown to modestly reduce joint pain in postmenopausal women. For example, in the Women's Health Initiative, they found that estrogen alone decreased the frequency and severity of joint pain, although it slightly increased joint swelling. These findings, however, are specific to postmenopausal women and may or may not apply to all individuals with hypermobility.
[07:44] As I mentioned, estrogen is very important for connective tissue repair. It influences collagen production, tissue elasticity, and cellular activity within ligaments and connective tissues. It promotes the synthesis of extracellular matrix components such as collagen, which are essential for ligament strength and structural integrity. High levels of estrogen, however, particularly during certain phases of the menstrual cycle, can actually reduce ligament stiffness by inhibiting lysyl oxidase, an enzyme critical for collagen cross-linking. This can actually lead to increased ligament laxity and a reduced ability to tolerate mechanical loads, potentially delaying repair and increasing the risk of re-injury or rupture in ligaments like the anterior cruciate ligament, otherwise known as the ACL.
[08:31] Progesterone also plays a really significant role in connective tissue by influencing collagen synthesis, extracellular matrix remodeling, and tissue mechanical properties. Research shows that progesterone can decrease collagen production and increase tissue softness by altering extracellular matrix composition and regulating enzymes such as matrix metalloproteinases, or MMPs, which are involved in collagen turnover. Progesterone has also been shown to modulate the balance of collagen and elastin fibers in connective tissues, often reducing cross-linking and mechanical strength. While these effects are beneficial in pregnancy and other contexts, they may contribute to tissue laxity or slower repair in other scenarios. The effect of progesterone varies depending on the tissue type, hormonal levels, and physiologic conditions. Overall, progesterone's regulation of MMPs is highly context-dependent, supporting connective tissue remodeling in some cases but preventing excessive degradation in others.
[09:30] Progesterone also plays a significant role in promoting sleep by influencing brain pathways and neurotransmitters. It enhances sleep through the activity of GABA, a calming neurotransmitter that reduces anxiety and promotes relaxation, which helps people fall asleep more easily and stay asleep longer. Oral progesterone in particular is really helpful for sleep and can actually mimic the effects of sedatives like benzodiazepines. Progesterone can actually improve sleep architecture by increasing slow-wave or deep sleep and reducing wakefulness after sleep onset, particularly in postmenopausal women or those experiencing fragmented sleep. It also may help with conditions like sleep apnea by improving respiratory drive and stabilizing breathing patterns.
[10:15] Low progesterone levels during menopause, however, are associated with insomnia, shorter sleep duration, and lower sleep efficacy, highlighting the importance of maintaining healthy sleep cycles. I think we all know the importance of sleep when it comes to pain. We often see a painsomnia type of forward-feed cycle where we have pain and therefore we don't sleep well, and when we don't sleep well, we end up having more pain.
[10:41] Sometimes progesterone is administered through an IUD. Progesterone through something like an IUD — an intrauterine device — can be a safe and effective option for managing heavy menstrual bleeding, for example, in people with vascular EDS. There are studies that have suggested a possible link between IUDs and immune-related illnesses or connective tissue disorders, but we definitely need more evidence. There are also rare adverse events such as uterine perforation that may pose a slightly higher risk for people with fragile tissues, such as those with connective tissue disorders. It's very important to weigh the risks and the benefits of a progesterone IUD before you decide if that's a good choice for you.
[11:20] It is very important to use progesterone alongside estrogen in hormone replacement therapy if you have an intact uterus in order to protect against endometrial cancer. Estrogen alone can cause the uterine lining, or the endometrium, to thicken excessively, increasing the risk of cancer. Adding progesterone can help counteract this effect by regulating endometrial growth and inducing shedding of the lining, mimicking a natural menstrual cycle.
[11:45] It's important to consider topical estrogen as a separate entity because unlike systemic hormone replacement therapy — like oral pills or patches — low-dose topical estrogen has localized effects. It can help relieve vaginal dryness, itching, or discomfort, and it has minimal absorption into the bloodstream. As we discussed with Dr. Kelly Casperson, localized topical estrogen can also help reduce the risk of bladder infections. This localized approach reduces systemic risks associated with hormone replacement therapy, such as blood clots or cardiovascular issues, making it a safer option for some women.
[12:21] So now let's talk a little bit about testosterone. As I mentioned during the podcast interview with Dr. Goldstein, I was a patient of his a number of years ago, and at that time he did prescribe testosterone for me. I did find it to be an effective therapy. However, some of my doctors were less comfortable with me continuing on that. So I do want to dive into this in more detail because I do think it's a really, really important conversation.
[12:45] Testosterone plays a significant role in the maintenance and regulation of connective tissues, including cartilage, tendons, and ligaments. It influences collagen production, which is vital for the structural integrity and strength of connective tissue. There are studies that suggest that testosterone can promote cartilage formation and protect against cartilage degradation, potentially reducing the risk of conditions like osteoarthritis. Testosterone has been shown to affect the balance of collagen and elastin in vascular connective tissues, contributing to tissue stiffness or elasticity depending on levels. The role of testosterone in connective tissue disorders like EDS desperately needs more study.
[13:26] Low testosterone levels have been associated with an increased likelihood of developing arthritis. Studies suggest that testosterone replacement therapy can enhance bone density and muscle mass, which may indirectly improve joint stability and reduce strain on connective tissues. Testosterone also has anti-inflammatory properties, reducing levels of inflammatory cytokines like TNF-alpha and interleukin-1-beta. This may also help reduce the chronic inflammation that we often see associated with connective tissue disorders. Testosterone contributes to overall tissue repair and vascular health by improving blood supply and promoting healing.
[13:58] Testosterone can improve bone density in patients with connective tissue disorders, particularly if people have low testosterone levels to begin with. Testosterone stimulates osteoblast activity — the bone-forming cells — and reduces osteoclast activity — the bone-resorbing cells — helping to maintain the balance of bone turnover. Studies show that testosterone replacement therapy can significantly increase bone mineral density, especially in the lumbar spine, during the first year of treatment. This improvement may be particularly beneficial for individuals at risk of osteoporosis or fractures, which are common concerns in people with connective tissue disorders like EDS.
[14:45] Testosterone replacement therapy can also enhance the expression of growth factors like IGF-1 and TGF-beta, which promote bone formation and reduce inflammation. While testosterone replacement therapy has shown clear benefits for improving bone mineral density, it is usually used alongside other treatments such as bisphosphonates for optimal management of osteoporosis or related conditions.
[15:10] So while there is potential therapeutic benefit for testosterone in connective tissue disorders, much more targeted research is needed in order to fully understand its efficacy and safety in this context.
[15:21] It's important to understand that testosterone replacement therapy has potential side effects, and those should be carefully considered, particularly in patients with connective tissue disorders. Some of the common side effects include acne, oily skin, and worsening sleep apnea. We can also see increased red blood cell production, which raises the risk of blood clots, strokes, and cardiovascular events due to thicker blood. Other potential risks include testicular atrophy — where the testicle actually shrinks — and infertility, because testosterone replacement therapy suppresses the natural production of testosterone and sperm.
[16:10] For men who have prostate conditions, testosterone replacement therapy can exacerbate symptoms of benign prostatic hyperplasia — that's where the prostate gets enlarged and can obstruct the outflow of urine, causing men to go to the bathroom frequently and to experience urinary hesitancy. We also can see increases in prostate-specific antigen levels, which is something that we use to monitor potential risk for prostate cancer. The evidence on the direct link to prostate cancer with testosterone replacement therapy remains inconclusive. My urologist husband, who specialized in advanced prostate cancer and did a lot of robotic prostatectomy surgeries, would definitely want to point out that a critical component of prostate cancer therapy is testosterone-blocking drugs.
[17:07] Patients with preexisting conditions like cardiovascular disease or untreated sleep apnea may also face heightened risks due to testosterone replacement therapy. So a thorough medical evaluation and ongoing monitoring are essential.
[17:20] Speaking of monitoring, it's very, very important that people have careful and regular monitoring when they're on hormone replacement therapy in order to ensure safety and efficacy. Some of the things that are recommended include: number one, testosterone levels. It is important to monitor testosterone levels while on testosterone replacement therapy. Of course, the level should be checked before initiating any kind of therapy, but then again it should be checked about every 3 to 6 months or so. Once you've reached a desired range, then you can probably check every 6 to 12 months. The lab should adjust for females and use mass spectrometry in order to monitor and measure testosterone.
[18:05] I recently had my testosterone level checked. My PCP wrote the order for it. I definitely don't think that she has any kind of specialization in this, and the lab did do the correct type of test. But it is important to be aware of that. If your doctor is not a hormone specialist, you may want to point out that it is important that they have checked the box indicating you are female, and that they do need to use mass spectrometry in order to check the levels appropriately.
[18:31] It is also important to monitor bone health while you're on testosterone replacement therapy. You can assess your bone mineral density beforehand and at intervals of 1 to 2 years, depending on how your bone density is and whether or not you're at increased risk of osteoporosis. It's also really important to monitor your hemoglobin and hematocrit levels every 3 months or so after starting therapy to make sure that you don't get levels that are too high. This can be checked as a standalone hemoglobin and hematocrit test, or it can be checked through a CBC — a complete blood count. If you do develop polycythemia, which is where you get higher levels of hemoglobin, hematocrit, or red cells in the blood, then you may require a dose adjustment, or you may require therapeutic phlebotomy, where they take out some blood periodically so you don't have quite so many red cells in your body and your blood doesn't become too thick.
[19:28] It's also important for males to conduct regular prostate-specific antigen — or PSA — testing and digital rectal exams. PSA testing doesn't always detect prostate cancer, so the digital rectal exam is also very important to monitor for prostate abnormalities, especially for men over 40 or with a family history of prostate cancer.
[19:48] In terms of the cardiovascular risk associated with testosterone replacement therapy, it's very important that your blood pressure be monitored, that your lipid profiles be monitored, and also to watch for signs of venous thromboembolism. Venous thromboembolism refers to when you get a blood clot in a vein. If you get a blood clot in a vein, this can be particularly dangerous because that blood clot can travel up into your heart and actually can go out into your lungs, causing what's called a pulmonary embolism, or PE, and that can be a life-threatening event. A pulmonary embolism can be fatal. So this is extremely important to monitor for signs of thromboembolism, which usually presents as localized pain in the lower legs. Patients with preexisting cardiovascular disease or risk factors should be really closely observed.
[20:37] It's also important to have liver function tests checked periodically because testosterone therapy can affect metabolism in the liver. Many people also recommend screening for and monitoring exacerbation of any sleep apnea — that's where you hold your breath in your sleep — especially in people who are predisposed to respiratory problems.
[20:56] It's very important to document improvements in your symptoms, such as energy, muscle strength, and pain relief, to evaluate the effectiveness of therapy. You may need to adjust the dosage if symptoms persist despite normalization of testosterone levels. You want to make sure that you're optimizing the benefits of testosterone therapy while minimizing the risks, especially in people with connective tissue disorders. You may need to adjust the dose if you have inadequate symptom improvement, if you have persistent symptoms of low testosterone such as fatigue, weakness, depression, loss of libido, or poor pain control, or if you have symptoms of overdose such as acne, oily skin, irritability, or aggressive behavior.
[21:38] We're going to take a quick break, and when we come back, we're going to talk a little bit more about testosterone. We're going to talk about hormone replacement therapy in menopause. We will talk about gender-affirming hormone therapy. And lastly, we will talk about hormones and mast cells. We'll be right back.
[22:48] Okay, so let's quickly talk about some precautions with testosterone replacement therapy. We went into this a little bit, but I just want to point out that it's really important before initiating therapy that you mention to your doctor if you have a history of a clotting disorder such as Factor V Leiden or protein C or S deficiencies. These are things that hopefully your doctor will be asking you about, but just to be on the safe side, make sure that you point these out. Also point out other potential risk factors such as obesity, smoking, a sedentary lifestyle, cardiovascular disease, or if you've ever had a stroke in the past. Some doctors strongly recommend avoiding smoking and excessive alcohol consumption because those factors can also exacerbate clotting risk. You always want to use the lowest effective dose of testosterone to minimize side effects while achieving therapeutic goals.
[23:39] For physicians that are listening, it's important to be aware of the symptoms of blood clots, such as swelling, redness, or pain, which can indicate a deep venous thrombosis or a blood clot in the legs. If you get sudden shortness of breath, chest pain, or coughing up blood, those can be signs of a pulmonary embolism — when the clot goes from the legs into the lungs — and it's very important to seek immediate medical attention if any of those things occur.
[24:05] So that listener that I was mentioning earlier, and also this question has come up a lot in the thread about the testosterone post — a lot of people are wondering, how can I find someone that might prescribe testosterone for me? So first of all, I would caution you against starting with the therapy that you want and then trying to find someone to prescribe it for you. I know that there are different platforms available online now where you can decide, "I want to get a prescription for testosterone," or whatever the drug might be, and then you can go online and find someone to prescribe it. I worry about those platforms, though, because I feel like they may or may not do their due diligence. I have a lot of patients who have visited platforms like that for different types of care. There are platforms like that now with gastroenterologists, gynecologists, or endocrinologists, and I feel like they are designed to write these prescriptions and not necessarily do a really thorough evaluation. Oftentimes they actually benefit from prescribing the medications to you because they have the ability to dispense those medications as well. So you need to be particularly cautious about that.
[25:17] I will talk a little bit about places where you might be able to get someone to do a proper evaluation about whether you're a good candidate for testosterone replacement therapy. First off, you might want to consider seeing an endocrinologist. Endocrinologists focus on hormone-related conditions. Of course, today we're focusing on estrogen, progesterone, and testosterone, which are considered "sex hormones." We also know they're very important for the brain, but endocrinologists are also going to work a lot with thyroid hormone and diabetes, because that's definitely an area of their expertise. So it is very possible that you go to an endocrinologist whose practice is 99% focused on diabetes and the last 1% perhaps focused on thyroid disorders. They may actually not be that well-versed in testosterone, and they also might not be really willing to do a proper and thorough evaluation.
[26:22] Sometimes endocrinologists follow pretty strict diagnostic criteria and guidelines and may or may not be willing to actually look to see if you have a testosterone insufficiency, or if your levels are suboptimal, and what the risks and benefits are of prescribing. I saw an endocrinologist for my low bone density back when I was in Wausau, and again here after I moved to Colorado, and in both of those instances, I feel very confident that they would not have wanted to discuss testosterone with me.
[26:57] Urologists are very experienced in diagnosing and managing low testosterone. Dr. Kelly Casperson and Dr. Irwin Goldstein are both urologists who I had on the podcast recently, as I mentioned earlier, and they are probably amongst the group of doctors who are particularly skilled at prescribing testosterone, especially in men. I would say that probably a lot of urologists are not as well-versed in the role of testosterone in women and the indications and contraindications in women. They may, however, be more flexible when it comes to prescribing testosterone replacement therapy as compared to endocrinologists.
[27:34] You could also consider going to a men's health clinic or a women's health clinic. Sometimes these clinics that specialize in men's health or women's health specifically may actually do more comprehensive hormone evaluations and treatment plans tailored to your needs. I do worry, however, because a lot of these clinics will actually dispense the medication to you, so they have a conflict of interest — they are going to get higher levels of reimbursement and may actually make more money on dispensing these medications than they make on the visits themselves. So I would definitely ask when you call whether they dispense the medications themselves, and really try to get a good sense of how thorough they are with their evaluations.
[28:20] I doubt that they're going to answer this question directly, but what I would love to know is how often do people leave that clinic without a prescription for testosterone replacement therapy. If most everyone leaves with a prescription, I would worry more that they are not being careful enough in their assessments.
[28:40] There are a lot of different administration options for testosterone, including injections, gels, and pellets — but we'll talk more about pellets in just a few minutes.
[28:49] You could also talk to your PCP, like that listener's question was addressing. A PCP can evaluate your symptoms and perform some initial testing. However, they are unlikely to be a specialist in this topic, so it's important to consider whether they are really fully versed in the indications and contraindications for testosterone replacement therapy.
[29:12] If you do go to a testosterone replacement therapy clinic specifically, really look for ones that are reputable and have experienced providers who specialize in hormone therapy. You want to make sure that they are doing thorough evaluations, that they're doing lots of blood tests, and looking at total and free testosterone levels before starting treatment. Unfortunately, hormone mills tend to advertise very, very heavily. I'm sure you've heard these commercials on TV, and they likely have a really low threshold for prescribing — as I mentioned — because they have a conflict of interest.
[29:44] So when you're listening to those commercials, really pay attention. If they say something like, "Your evaluation is free if you sign up for testosterone at your first appointment," then that's a really important indicator that they are making money on the actual prescription, and therefore they might not be as thorough and as cautious as they should be with prescribing testosterone replacement therapy.
[30:07] Make sure you know what your doctor's credentials are — very, very important. Look at the initials after the name because that's a lot more informative. A lot of people can call themselves "doctor," so that doesn't necessarily mean that they're an MD. You don't necessarily need an MD — it could be a DO, it could be a nurse practitioner. You could go to a nurse practitioner or a physician's assistant who is extremely knowledgeable about hormones. I would probably ask when you call what that person's training is and what specific training they have in hormones. If they have done some functional medicine training or integrative medicine training, or they've done training through A4M, for example, they may be extremely knowledgeable about hormones, and that might be a really good way to go.
[30:53] You definitely want to prepare yourself for a thorough medical history review, physical examination, and lab testing. Ideally, they're actually testing your testosterone level on at least two occasions. By consulting with specialists or reputable clinics, you are much more likely to have testosterone replacement therapy prescribed in the most safe, evidence-based way.
[31:15] I do want to discuss briefly about pellets. Pellets are little capsules, if you will, that are injected into the body. This can be a method of administering hormones — estrogen, testosterone, and probably other things as well. Those are the two we're going to talk about here today. One of the advantages of pellets is that — they use a needle, and the pellet is inside the needle, so as you can imagine, the needle is quite big, especially for men getting testosterone therapy, because in that case the pellet itself is going to be a lot larger — you don't have to worry about daily administration of a topical solution. You don't have to worry about giving yourself injections a couple of times a week. So there are some definite advantages.
[32:03] There are definite disadvantages as well. It's important to be aware that once the pellet is injected, you can't adjust the level. So if it's too high, you just have to wait until it wears off, which takes several months. There are several long-term risks associated with testosterone pellets that are really important to consider. The cardiovascular risks — like the risks of heart attacks, strokes, and blood clots — are particularly relevant if you get a testosterone pellet and the level is too high. You also want to think about the other risks we discussed, such as prostate health and localized risks. The implantation procedure for testosterone pellets carries the risk of infection, scarring, or pellet extrusion — it can dislodge or fall out — and those complications can require additional intervention.
Long-lasting pellets make it difficult to adjust the dosage quickly if you get side effects, and it can also be very challenging to adjust the dose even if it's too low. Usually you have to wait until the next cycle in order to adjust. It is also important to consider that your doctor might be making extra money when they inject pellets, and this may cloud their judgment — even subconsciously — and make them more prone to recommend pellets to you. So it's important to be aware of that.
[33:28] Now let's shift gears a little bit and talk about menopause. As I've mentioned before, and you'd probably guess based on my age, I am postmenopausal. As I mentioned earlier, I am on low-dose hormone replacement therapy that was started shortly after I entered menopause. I do think that in my case, this has helped me feel better in my body and helped my joint pain. I have noticed as well in a lot of my patients that it does seem that hormone replacement therapy after menopause is beneficial in terms of pain levels and ability to sleep. Of course, it helps with things like hot flashes.
[34:05] But menopause really can alter connective tissue due to the sharp decline in estrogen levels. As I mentioned earlier, estrogen plays a critical role in maintaining the structure, function, and turnover of our connective tissues. Estrogen is essential for collagen synthesis, which is a key protein providing strength and elasticity to connective tissues such as skin, tendons, ligaments, and bones. During menopause, reduced estrogen levels lead to decreased collagen production and impaired connective tissue repair, resulting in weakened structures. This manifests as thinner, less resilient skin, reduced ligament and tendon strength, and decreased bone mineral density, increasing the risk of fractures and injuries.
[34:47] Also, testosterone deficiency is associated with increased production of inflammatory cytokines like interleukin-6 and TNF-alpha, which further accelerates tissue degradation and delays healing processes. Hormone replacement therapy has been shown to partially mitigate these effects by improving collagen synthesis, tissue elasticity, and bone density. Hormone replacement therapy, though, must be carefully evaluated on an individual basis.
[35:09] Hormone replacement therapy also helps preserve bone mineral density, which is important in people with connective tissue disorders because we may be at risk of osteoporosis and related fractures. There are some people that even advocate using testosterone topically on our skin, and this can help further mitigate age-related changes in our skin by increasing collagen levels, improving elasticity, and reducing wrinkles.
[35:40] So while hormone replacement therapy can help support our connective tissue health, it's also important to consider the risks, which we will discuss next.
[35:46] We already discussed the potential benefits of HRT on connective tissue. HRT can also help alleviate menopausal symptoms such as hot flashes, night sweats, and vaginal dryness, and may reduce the risk of osteoporosis and fractures. It is also important to consider, though, that HRT can increase the risk of stroke and blood clots, and also gallbladder disease and possibly breast cancer. These risks might be higher if HRT is initiated more than 10 years after menopause or after age 60. The evidence does suggest, though, that when started near menopause — under the age of 60 or within 10 years of menopause — the risks are lower, and HRT may even reduce all-cause mortality and cardiovascular disease in some cases. It's really important to have a thorough conversation with your healthcare practitioner in order to decide what the personalized treatment plan is that's best for you.
[36:46] Okay, so now let's talk about menarche, which is the onset of menstruation — the beginning of menstrual cycles. This is an important hormonal shift that can impact connective tissue in a wide variety of ways. In the many, many patients and clients that I have seen, it is super, super common for people to talk about how their symptoms changed quite dramatically after menarche. Menarche can happen at varying ages — it can happen at 10, 12, 13, even 16. And sometimes people don't make that association at first. It's only when we have further, deeper discussions and we go through their timeline that they realize that it did impact their symptoms.
[37:29] During puberty, we see a rise in estrogen and progesterone, which influences connective tissue remodeling, particularly through effects on collagen synthesis and the extracellular matrix. The extracellular matrix involves the collagen and other components outside of the cells that are very, very important for building tissue strength. As we talked about earlier, estrogen promotes the growth and elasticity of connective tissues, but it can also reduce tissue stiffness by inhibiting cross-linking enzymes, which can increase tissue laxity and actually can make you more susceptible to injuries during activities like sports or dance.
[38:04] Progesterone also plays a role by modulating connective tissue remodeling, often reducing collagen density and stiffness in specific contexts such as the endometrium during the menstrual cycle. Hormones like estrogen also regulate the expression of proteins such as connective tissue growth factor, particularly in tissues like the endometrium during post-menses repair. So these hormonal changes directly contribute to the dynamic remodeling of connective tissue during menarche and puberty, and this influences both reproductive health and musculoskeletal health.
[38:40] So let's talk about EDS or HSD symptoms and puberty. In pubertal females, it's not uncommon at all to see the worsening of EDS and HSD symptoms, and we often see relative improvement in males. This can be attributed to the massive differences in hormones once puberty hits. Prior to puberty, hormone levels are not that dramatically different between males and females, but after puberty, we see dramatic differences. Males generally benefit from testosterone, and females have estrogen and progesterone, which can contribute to worsening of symptoms. The benefits of testosterone — promoting collagen synthesis and muscle mass development — can also improve joint stability and reduce the severity of EDS or HSD symptoms. And these hormonal differences probably explain why post-pubertal males often report stabilization or improvement in symptoms compared to females.
[39:37] Next, let's talk about gender-affirming hormone therapy. I have discussed this with some of my colleagues, and we have all observed that trans women who are taking feminizing hormones such as estrogen generally tend to see a worsening of symptoms, whereas trans men or people who are taking masculinizing hormone therapy tend to see a benefit in their symptoms. And this makes sense based on what we discussed earlier. People who are taking feminizing hormones such as estrogen and progesterone are likely to see an increase in their symptoms related to connective tissue laxity, whereas people who are taking masculinizing hormones such as testosterone are likely to see the anti-inflammatory benefits, and they may also see the benefits related to increased muscle mass and increased tissue strength.
Hormonal changes from gender-affirming hormone therapy can also influence immune function. Particularly, we can see an exacerbation or triggering of autoimmune conditions like lupus in genetically predisposed individuals, especially if they're taking estrogen. Gender-affirming hormone therapy can alter connective tissue properties, bone health, and injury risk. So it's very important to be monitored closely by somebody with the proper expertise.
[40:56] Before we wrap up, the last topic we're going to cover is mast cells and hormones. I don't know about you, but I have definitely observed a connection between my hormones and my mast cells. Mast cells, which are key players in the immune system, are significantly influenced by sex hormones such as estrogen and progesterone. These hormones affect their activation, degranulation, and mediator release.
[41:21] Mast cells have hormone receptors on their surface. Estrogen enhances mast cell activity by binding to estrogen receptors. This leads to increased degranulation and the release of inflammatory mediators like histamine and leukotrienes. We particularly see this effect during hormone fluctuations, such as during the menstrual cycle or in pregnancy, and we can also see an exacerbation of mast cell-related conditions like allergies, autoimmune diseases, and endometriosis. Estrogen also increases mast cell recruitment and differentiation in certain pathological settings, which can contribute to inflammation.
[41:58] The role of progesterone is more complex. While progesterone can modulate mast cell activity positively by promoting vascular growth and tissue remodeling during pregnancy, it also has anti-inflammatory effects in some contexts. Progesterone can actually inhibit mast cell degranulation under specific conditions, which can help regulate immune responses. The interplay between these hormones and mast cells highlights their critical role in both physiologic processes and pathologic conditions.
[42:28] Testosterone also plays a significant role in modulating mast cell activity, primarily through its anti-inflammatory effects. Mast cells have receptors for testosterone as well as for estrogen and progesterone. Testosterone influences the behavior of mast cells in a tissue-specific and subset-dependent manner. Research suggests, though, that testosterone does not appear to significantly affect mast cell degranulation or their numbers in tissues. Its primary effects are on cytokine expression and immune modulation. So testosterone's potential to regulate mast cell-driven inflammation and immune responses may explain the massive difference we see between males and females when it comes to autoimmune conditions.
So remember, we want to think of sex hormones as actually being brain hormones. These hormones have many more effects besides on the reproductive system. Individualized care is really, really essential. A lot of people are hearing about the potential benefits of hormone replacement therapy or testosterone replacement therapy and are looking specifically for doctors who will prescribe these types of medications. Remember, though, it is very, very important that somebody do a thorough evaluation and make sure that you don't have contraindications to these types of treatments.
[43:47] One place that you might be able to find a provider who is more knowledgeable — if you are in menopause or perimenopause — is the Menopause Society, and the website is menopause.org. We will be sure to link that in the show notes. I know that one of the sponsors of You Are Not Broken is called Midi Health. I don't know anything about them. If you happen to know anything about them, have any positive or negative experiences, I would love to hear from you. I do always appreciate feedback and really appreciate knowing as much as possible about some of these options that are out there, because they may be wonderful options. But at the same time, we need to make sure that they are doing their due diligence. So if you happen to know of any online services that you would either recommend or not recommend, please be sure to send me a message. You can visit my website at bendybodiesspodcast.com to send me a message, or you can leave me a direct message on Instagram, LinkedIn, Twitter, or one of the other platforms that I'm on.
[44:52] As you may know, we always end our episodes with a hypermobility hack. My hypermobility hack is something that I already kind of mentioned during the episode. I just want to give another warning about hormone mills. Very, very important that you ask the right questions. So make sure that when you call before you make an appointment, you ask questions like: what are some of the contraindications to hormone replacement therapy? What are some of the contraindications to testosterone replacement therapy? And if they're basically telling you, "Well, there aren't any," then I wouldn't even go there, because it sounds to me like a place where most everyone is going to walk out with a prescription.
[45:31] So while it's important to avoid hormone mills, you also want to find somebody that is going to take a balanced approach. It may be kind of hard to do this. As we talked about, you might be able to visit an endocrinologist or a urologist or a gynecologist who has a special interest in hormones. But it's also important to consider that sometimes they take a very, very conservative approach. Sometimes visiting a functional medicine provider is a good option. You could go to ifm.org — that's the Institute for Functional Medicine — to find a functional medicine certified provider in your area. Make sure that you check out their credentials, though, because functional medicine involves a whole host of different types of training, and some people are probably very, very well-versed in hormones and others are not.
[46:21] You also want to see what their education and training was before they did their training through IFM, because that will also influence their lens when assessing you and the types of treatments they might prescribe. I would also recommend looking at what type of specialist the person is on the IFM website, because a lot of people can get certified in functional medicine. You might see chiropractors on the site, you might see nurse practitioners, you're going to see physician's assistants, MDs, DOs — a wide variety of people. So you want to make sure that you know what their background is, because that will influence their lens as well as the options they will be able to prescribe to you.
[47:03] Well, that wraps up this week's episode of the Bendy Bodies Podcast. I hope you found this helpful. Thank you for listening. You can help us spread the word about joint hypermobility and related disorders by leaving a review and sharing the podcast. This really helps raise awareness about these complex conditions. If you would like to dig deeper, you can meet with me one-on-one. Please check out the available options on the services page of my website at hypermobilitymd.com.
[47:31] You can also find me, Dr. Linda Bluestein, on Instagram, Facebook, TikTok, Twitter, or LinkedIn at hypermobilitymd. You can find Human Content, my producing team, at humancontentpods on TikTok and Instagram. You can find full video episodes up every week on YouTube at Bendy Bodies Podcast. To learn about the Bendy Bodies Program disclaimer and policy, submission verification and licensing terms, and HIPAA release terms, or to reach out with any questions, please visit bendybodiesspodcast.com. Bendy Bodies Podcast is a Human Content production. Thank you for being a part of our community, and we'll catch you next time on the Bendy Bodies Podcast.