Hormone Replacement Therapy & Progesterone: Why It Matters for Women's Health

Understanding the Role of Progesterone in Hormone Replacement Therapy (HRT) for Women: Levels, Roles, and Concerns for Women in Menopause

Hormone Replacement Therapy (HRT) has become a vital tool for women that are trying to manage the unwanted symptoms of menopause and improving their quality of life during what can be difficult period for many. There are several hormones at play in women and all have unique functions in the female body. These hormones are constantly fluctuating and when a woman hits perimenopause, they go haywire with some increasing, some decreasing and others becoming erratic. The major hormones that drive a women’s mental and physical health are Estrogen, progesterone, prolactin, hCG, FSH, LH, T3/T4 and testosterone. When that balance is upset, the side effects can be tough to handle.  Hot Flashes, Night Sweats, Mood Changes, Vaginal Dryness and Sleep Disturbances are some of the common side effects that women seek help with from doctors such as OBGYNs, endocrinologists and hormone replacement therapy specialists.

Among the key hormones involved in women’s health, progesterone is one that plays a crucial role, often alongside of estrogen. Understanding what optimal progesterone levels are, its physiological functions in the woman’s body, and the potential health consequences of imbalances are essential for an effective hormone therapy protocol and treatment. In this article, we’ll talk about the role of progesterone in HRT, focusing on optimal levels, its roles in women’s health, the impact of low levels, and the changes observed during menopause.  

How Progesterone Supports Women’s Health Across All Stages of Life

Progesterone, is considered a steroid hormone and is primarily produced by women in the ovaries by the corpus luteum after ovulation. Its primary job is to prepare the uterus for pregnancy by thickening the endometrial lining. It’s important for supporting pregnancy, which is why women undergoing IVF, for example, take progesterone to help prepare their body for implantation and to support the growing fetus. Beyond reproduction, progesterone exerts a significant influence on several different physiological processes.  

• Endometrial Regulation: Probably the most recognized role of progesterone is its interaction with the endometrium. The endometrium is the inner lining of the uterus that plays an important role in the menstrual cycle, pregnancy, and overall reproductive health for women. It counteracts the proliferative effects of estrogen, preventing excessive endometrial growth and helps to reduce the risk of hyperplasia and cancer. This is particularly important in HRT, where estrogen is often prescribed and taken by patients.  
• Neuroprotective Effects: Progesterone has been shown to have calming and has been known to help reduce anxiety (anxiolytic effects). It can also help contribute to mood regulation and may help to improve sleep quality, all side effects that many women experience in perimenopause and menopause. Progesterone is interesting in the fact that it interacts with GABA receptors in the brain. GABA receptors have several important roles such as they help Promote Relaxation & Reduce Anxiety by helping dampen excitatory signals, which reduces stress and anxiety levels. They also help to Regulate Sleep through the inhibiting of overactive neurons, which may contribute to better sleep quality and can even help initiate sleep for those that have a tough time falling asleep at night. They also Control Muscle Tone as GABA activity in the motor system helps prevent things like muscle spasms and tremors. Another important role is that GABA receptors help Modulate Mood & Emotion which can fluctuate significantly in women when their hormone levels are constantly changing.  This is one of the hardest symptoms to deal with as it often affects more than just the woman, but their families, friends and coworkers as well.  
• Bone Health: Progesterone also stimulates cells that help build bones called osteoblasts.  These are essential for bone formation, stimulating new bone growth as well as helping counteract bone loss that naturally occurs with aging, especially after menopause.  
• Cardiovascular Effects: While the effects of progesterone on CV health is complex and still being researched, studies have shown that progesterone may have some beneficial effects on cardiovascular health, including vasodilation as well as having potentially positive impacts on cholesterol and lipid profiles.

Progesterone Levels in HRT: Defining what “Good” levels are.

The million-dollar question is “what’s a good progesterone level for a woman?”   Trying to find out what the "ideal" progesterone level for a woman on HRT is not as simple as it might seems or people would like. It’s not a “one size fits all” approach. Unlike estrogen, where specific target ranges are often established, progesterone levels in HRT are more focused on the individual patient and are context dependent.  What’s considered a "good" level will vary and depend on factors like the type of HRT, the route of administration (oral, transdermal, vaginal), and the patient’s symptoms and risk factors.

Women are all unique and have different baseline progesterone levels. Factors like their age, menopausal status, and overall health will contribute to their specific needs. Some patients might need a higher dose for endometrial protection, while others may require lower doses in order to avoid side effects.   Sequential vs. Continuous is another factor. In sequential HRT, progesterone is administered for a specific period each month, whis is done to try and mimic the natural menstrual cycle of the woman, where in continuous combined HRT, progesterone is given daily alongside estrogen typically to help alleviate unwanted symptoms. The target progesterone levels for these patients will differ between these regimens.   

Also, different forms of progesterone affect absorption so the dose will depend on what type of medication the patient is taking and even what symptom they’re trying to deal with. Oral Progesterone (e.g., micronized progesterone) has what’s called a systemic effect and is often prescribed by physicians for sleep and anxiety benefits.  For many women HRT patients, a focus on endometrial protection is often the primary goal of taking progesterone. Thats why a doctor’s goal is normally to protect the endometrium from estrogen-induced hyperplasia, therefore, the level prescribed should be sufficient to achieve this protective effect and often require Micronized Progesterone (Prometrium).  It’s most recommended for endometrial protection due to it being bioidentical (structurally identical to the body’s own progesterone and well-tolerated with fewer side effects. The pros are it protects the endometrium effectively and supports sleep and anxiety relief (due to GABA receptor effects) as well as been shown to help lower risk of blood clots compared to synthetic progestins. Some of the Cons is that it may cause drowsiness (which is why its best taken at night) and some women have reported experiencing bloating or dizziness. When prescribed the typical dosage is usually 100–200 mg orally at bedtime, but this will be determined for each patient by their prescribing physician.

Topical or Transdermal Progesterone (creams, gels) on the other hand may have variable absorption rates and may not provide adequate endometrial protection. For others on IVF or fertility treatments, Vaginal Progesterone (suppositories) is directly absorbed by the uterus and is commonly prescribed.

How are Progesterone levels tested?

The question to determine the best way to check hormone levels will be patient specific. The 2 options are serum vs. salivary Levels.  Blood Test (Serum Progesterone Test) is the most common method. Progesterone levels measured through a blood test, can help a healthcare provider assess ovulation, fertility, pregnancy health, and hormone balance.  They are usually taken…

• Mid-Luteal Phase (Days 21-23 of a 28-day cycle) – To confirm ovulation.
• During Early Pregnancy – To assess if a woman’s progesterone levels are sufficient to support her during pregnancy.
• When on HRT – To monitor the effectiveness of medication and progesterone balance in hormone therapy.

Serum levels are more commonly used in clinical practice. Low levels may indicate anovulation, luteal phase defects, or hormonal imbalances where high levels may occur during pregnancy, with ovarian cysts, or with excessive progesterone supplementation.  Blood tests are considered the gold standard for assessing progesterone levels in most medical settings. Saliva or urine tests may provide insights but are generally not as reliable for diagnosing hormone imbalances or guiding HRT adjustments and often are not considered a reliable method for clinical testing due to possibly being unreliable.

While specific target ranges vary, the goal is to ensure that progesterone levels are adequate to prevent endometrial hyperplasia for women on HRT. For most patients on cyclical HRT, a mid-luteal phase serum progesterone level is aimed for, where lower levels are acceptable for those who are on a continuous combined HRT. HRT must be an individualized approach. Ultimately, the optimal progesterone level must be determined by a healthcare provider based on individual patient needs and careful monitoring.

Consequences of Low Progesterone Levels

Low progesterone levels, especially in the context of HRT, can potentially lead to several adverse side effects including but not limited to some of the following:  

• Endometrial Hyperplasia: The most significant risk of Low Progesterone for women is endometrial hyperplasia. This condition is characterized by an abnormal thickening of the uterine lining, which can progress to endometrial cancer if not monitored and treated.
• Breakthrough Bleeding: Low progesterone can lead to irregular or heavy menstrual bleeding, especially in sequential HRT.  
• Mood Disturbances: With low levels, progesterone's calming effect can be diminished, which can lead to increased anxiety, irritability, and mood swings.  
• Sleep Disruption: Low progesterone can contribute to a patient suffering from insomnia and poor sleep quality which can then exacerbate hormonal fluctuations.  

Progesterone and Menopause

For women, perimenopause and menopause can be a difficult period of adjustment to how the body acts and responds. During this time, the ovaries gradually begin to cease production of both estrogen and progesterone. This decline in these 2 hormones can lead to a range of both symptoms and physiological changes.  Typically, we see the following in women undergoing menopause.

• Declines in Progesterone Levels: Progesterone production drops significantly during perimenopause and reaches very low levels after menopause. This is due to the ovarian follicles ceasing to ovulate which is when progesterone is mainly synthesized by the woman’s body.  
• Impact on Endometrium: This rapid decline in progesterone generally leads to a thinning of the endometrial lining in the uterus.  
• Symptom Contribution: This combination of both estrogen and progesterone levels being lowered may produce several common symptoms during menopause, like hot flashes, night sweats, mood swings and vaginal dryness.
• HRT's Role: The goal of starting HRT for women struggling with menopause and hormonal imbalances is to replace the declining hormones and elevating them to more suitable levels, alleviating these unwanted symptoms and hopefully improving the patient’s quality of life. Progesterone can play a critical role in HRT, particularly for women with a uterus, to counteract the effects of estrogen and prevent endometrial hyperplasia.  

Optimizing Progesterone Levels on HRT

Since everyone is different, there may be a period of adjustments that have to take place. Effective HRT management requires a collaborative approach between the patient and healthcare provider, and this means scheduling follow up bloodwork to assess the effectiveness of treatments on hormone levels and assessment of symptom resolution.  A wise approach to hormone replacement therapy for women, is to ensure that there is regular monitoring of hormone levels and endometrial health, which we know is crucial to ensuring “good” progesterone levels and to help prevent complications from arising. Individualized Dosing for patients is important as HRT regimens must be tailored to meet the patients’ individual needs and take risk factors into consideration before coming up with ta protocol and dispensing medication to the patient. Open communication with your doctor about symptoms, concerns, and potential side effects is essential and with a good approach and healthcare team behind the patient, it helps to ensure both efficacy and safety of the HRT protocol.

 

All in all, progesterone is a vital hormone in HRT, playing a critical role in endometrial protection and overall well-being for women. Understanding its functions, optimal levels, and the consequences of imbalances is essential for effective HRT management. By working closely with healthcare providers and adopting a holistic approach and maintaining healthy lifestyle habits, including having a balanced diet, engaging in regular exercise, and practicing stress management techniques, can help support overall hormonal balance.   With an intelligent approach, women can navigate menopause with greater confidence and improve their quality of life.  

TRT and Blood Pressure: Does Testosterone Raise or Lower Hypertension Risk?

The Effects of Testosterone on Blood Pressure in Hypogonadal Men

The Complex Relationship Between Testosterone and Blood Pressure in Hypogonadal Men

As more and more men are looking to turn back the clock by starting hormone replacement therapy regimens, there are some concerns regarding the safety and potential for negative side effects from taking medications to influence hormones, specifically testosterone and estrogen in hypogonadal men. Testosterone replacement therapy (TRT) has been widely studied for its benefits in men with low T, or hypogonadism which is a condition characterized by low testosterone levels. The range may vary based on age and other factors; however the typical standard has been between 250-1000 ng/dl. While TRT has been shown to improve several different aspects of health, including muscle mass, strength, libido, bone density, and mood, its effects on blood pressure (BP) still remains a subject of debate amongst those in the medical profession. Patients often ask us if “taking testosterone will increase their blood pressure?” Some studies have suggested that TRT may contribute to hypertension, while others indicate a potential for BP reduction. With conflicting evidence, we have to ask what’s the evidence and why is there a discrepancy between conclusions?  In the following blog post, we’ll investigate the findings from multiple studies to provide a comprehensive overview of the relationship between testosterone and blood pressure in hypogonadal men and how TRT can either contribute to the increase or decrease in BP for patients.

Testosterone and Blood Pressure: Conflicting Perspectives

The effects of TRT on BP have been examined in multiple studies from various researches with differing conclusions. Some reports, such as those from Geoffrey Hackett et al., suggest to us that testosterone undecanoate (TU) therapy may be associated with significant reductions in both systolic and diastolic blood pressure as well as pulse pressure in hypogonadal men, regardless of whether or not they are on any antihypertensive therapy.  Antihypertensive therapy can include medications like diuretics, (ACE) Inhibitors, Angiotensin II Receptor Blockers or beta blockers. In their study, the findings indicate that men who were never on antihypertensive medications experienced BP reductions of -12.5 mmHg (systolic), -8.0 mmHg (diastolic), and -6.0 mmHg (pulse pressure) at final assessment. In contrast, their study showed that the men who did not receive TU showed increases in blood pressure over time.

However, a randomized controlled trial performed by Olesen et al. presented a completely different perspective from Hackett. This study found that men with opioid-induced androgen deficiency who received TRT experienced an average systolic BP increase of 6.2 mmHg, compared to a 7.0 mmHg decrease in the placebo group. Notably, men with higher hematocrit levels and elevated body mass index (BMI) appeared more susceptible to BP increases. These findings suggest that hematocrit levels may modulate BP responses to TRT but it also needs to be stated that these patients all had low T that was a result of taking opioids and not reflective of most typical cases of androgen deficiency.  It’s also important to ask what were the patients testosterone levels PRIO to their opioid dependency? Did they take a Low T test prior or is the reading of low testosterone post dependency the first time their hormone levels were checked? We do know that that heroin and opioids will lower testosterone levels however having a baseline reading that can be validated both before and after is important for researchers to determine valid conclusions and a credible hypothesis.

Hematocrit and Its Role in BP Regulation

One of the primary concerns with TRT is its potential to elevate hematocrit, which can increase blood viscosity and raise BP.  Testosterone therapy has been known to cause secondary erythrocytosis which can cause symptoms of hyperviscosity, such as headaches, low energy or fatigue, blurry vision and even paresthesias. If a patient on TRT has hematocrit levels of over 54, they should consider taking measures such as reducing their dosage of testosterone, staying well hydrated and in some cases many doctors will even recommend therapeutic phlebotomy.  Elevated hematocrit has been identified as an independent risk factor for stroke, particularly when combined with high blood pressure. This is the mechanism that explains why some men on TRT can experience increased BP, as seen in Olesen et al.'s study. However, the findings from Hackett et al. indicate that hematocrit was not significantly associated with BP changes in their cohort, suggesting that the relationship may vary based on individual physiological responses. Factors like genetics, age and overall health and fitness levels as well as diet and other lifestyle factors could all potentially influence BP responses to men on TRT and need to be studied further.

Mechanisms Behind Testosterone's BP Effects

Its hard for most people to process why you can have multiple studies with differing results. The mixed findings regarding TRT and BP can potentially be attributed to several different physiological mechanisms, such as:

1. Endothelial Function Improvement: Testosterone has been shown to enhance endothelial function by reducing oxidative stress and increasing nitric oxide production, which promotes vasodilation and lowers BP. The endothelium is the thin layer of cells that line the inside of blood vessels and are key in regulating vascular health. They help to maintain blood flow, vascular tone, and overall cardiovascular function.
2. Reduction in Insulin Resistance: Some studies indicate that TRT decreases insulin resistance, a factor that is often linked to hypertension. Insulin resistance is a condition where the body's cells become less responsive to insulin, the hormone that helps to regulate blood sugar (glucose) levels.
3. Aldosterone Suppression: Testosterone may lower aldosterone levels, by reducing sodium retention in the body and thus lowering blood pressure. Aldosterone is a hormone made in the adrenal glands and helps with regulating blood pressure, sodium (salt), and potassium levels in the body. It is part of the renin-angiotensin-aldosterone system (RAAS) and works by increasing sodium and water retention (raising blood pressure), Promoting potassium excretion through urine and Autonomic Nervous System Regulation: TRT has been associated with improved autonomic function, which could contribute to better BP control.

The Impact of TRT on Enhancing the Effects of Antihypertensive Therapy

TRT’s interaction with antihypertensive medications is another important consideration for men with BP concerns who may also be on hormone therapy. The long-term study by Hackett et al. found that for men who are receiving both TRT and antihypertensive medications, BP reductions were more pronounced than for those in the placebo group. Additionally, they reported that 16.4% of men on antihypertensive therapy at baseline discontinued their medication by the study's end, which suggested an additive or synergistic effect of TRT on BP regulation based on their conclusions.

Blood Pressure Monitoring and Safety Considerations

Its hard for patients to determine the potential effect that TRT may have on their BP prior to starting treatment. So, given that the potential for TRT to both raise and lower BP depending on individual factors, monitoring by a licensed and experienced healthcare provider is essential. A solitary BP reading is often unreliable due to natural fluctuations throughout the day. To get a true idea of one’s blood pressure, there should be multiple reading throughout the day over a course of several days.  For example, the British Hypertension Society recommends a BP target of <140/90 mmHg, with ambulatory blood pressure monitoring (ABPM) being the “gold standard “for diagnosing hypertension. TRT patients should undergo regular BP assessments, including hematocrit monitoring via blood tests, to mitigate risks associated with elevated blood viscosity.

How To Determine if TRT Will Impact Your Blood Pressure

Unfortunately, as we have seen, the effects of testosterone on blood pressure in hypogonadal men is both complex and is often influenced by multiple different factors, which will include things like baseline BP, hematocrit levels, BMI, and whether a patient is concurrently on antihypertensive therapy. Men how have taken tests for low T and have been diagnosed with hypogonadism need to assess their BP as part of determine the benefits of TRT.  While some studies demonstrate a clear BP-lowering effect of TRT, particularly in men with higher baseline BP, other studies highlight the potential risk of BP elevation when taking testosterone, particularly for those patients who already have increased hematocrit levels. That’s why we recommend individualized monitoring and patient-specific management strategies for patients on TRT. These are both crucial steps for optimizing the benefits of TRT while minimizing cardiovascular risks for patients. By understanding your risk factors an experienced healthcare provider may also be able to use that information to determine the best protocol to help ensure you get the most out of your hormone therapy while minimizing risks.

Learn more about us at NovaGenix here and see how TRT can impact your life.