In this last edition of the 2025 WAPO Blogs and Vlogs series featuring Marc Casas Boj, we will cover the important topic of pain and sleep issues in pituitary and adrenal conditions. Marc Casas Boj is a research psychologist specializing in psychoendocrinology at the Germans Trias I Pujol Health Research Institute in Barcelona, Spain. We are thrilled for him to share his expertise and provide practical guidance to support patients in coping with these symptoms.

How common are chronic pain and sleep issues in patients with pituitary and adrenal disorders?

Marc began by explaining that chronic pain and sleep problems are surprisingly common in people living with pituitary and adrenal disorders. To understand why, he introduced the field of psychoneuroendocrinology, which examines the complex interactions between hormones and behavior. As these disorders are multisystemic, sleep quality and pain are often a direct expression of how hormonal dysregulation impacts the central nervous system. Cortisol, for example, follows a circadian rhythm, usually peaking in the morning and reaching its lowest point around the onset of sleep or early in the night. When this rhythm becomes imbalanced, the consequences for both pain and rest can be significant.

Studies have shown that among newly diagnosed acromegaly patients, up to 70% have sleep apnea, 72% experience widespread pain, and 25% report chronic pain. In Cushing’s syndrome, many vertebral fractures go undetected until imaging shows multiple micro-fractures, even when patients report ongoing pain. Even in hypopituitarism and other conditions involving a hormone deficiency, patients frequently experience sleep disturbances and pain. This indicates that these symptoms are not secondary or psychological, but may be a direct result of the disease and its multisystem hormonal dysregulation.

Marc concluded by pointing out that this evidence aligns with what is seen in everyday clinical practice. When specific sleep questionnaires are used, most people with pituitary and adrenal disorders report difficulties falling asleep, staying asleep, or achieving rest that is restorative.

 How do stress hormones (such as cortisol) and other hormones specifically impact sleep architecture and pain sensitivity?

When it comes to sleep architecture, our circadian rhythm tells the body when to activate and when to rest and cortisol plays a central role as the body’s activation hormone. Cortisol should drop sharply at night so that the brain can enter rest mode, but in patients with pituitary and adrenal disorders, the hypothalamic–pituitary–adrenal (HPA) axis becomes dysregulated, meaning cortisol remains elevated. This misalignment, combined with other hormonal disturbances, disrupts the suprachiasmatic nucleus, which is the brain’s internal clock that governs the sleep-wake cycle. According to Marc, when the brain receives this inappropriate activation signal at night, it interprets it as stress or an ongoing alert. As a result, sleep architecture becomes fragmented and patients struggle to fall asleep, stay asleep, and access the deep, restorative phases of rest.

Marc then addressed how cortisol affects pain and mood. Glucocorticoids like cortisol act as powerful, natural anti-inflammatories, and their effects follow an “inverted U” pattern. On a graph with pain perception on the Y-axis and cortisol levels on the X-axis, both too little and too much cortisol increases pain, but for different reasons. Too little cortisol (i.e. in those with adrenal insufficiency), leads to the body losing its anti-inflammatory protection, resulting in increased inflammation and pain sensitivity. When there is too much cortisol, (i.e. in those with Cushing syndrome), the issue shifts to the brain, as prolonged glucocorticoid toxicity affects key regions like the hippocampus and amygdala, which regulate emotion, fear, and stress. This causes the brain to amplify pain signals, making even mild discomfort feel more severe. So both very low and very high cortisol levels can heighten pain, either through inflammation or through altered pain processing in the brain.

How does chronic pain and sleep issues impact a patient’s quality of life and overall wellbeing, and how does this relate to mood, anxiety and depression?

Marc gave an overview of the real cost of hormonal imbalances seen in these disorders. He noted that chronic pain and insomnia are not just physical symptoms. They often become the driving forces behind a vicious cycle that affects nearly every part of a patient’s life. Chronic pain and sleep issues add a significant emotional and mental burden. When hormones are disrupted and when sleep is already non-restorative, the brain is one of the earliest systems to suffer. This is why anxiety and depression frequently emerge alongside pain and fatigue.

An imbalance in the HPA axis disrupts sleep and heightens pain perception. In turn, this worsens mood, increases fatigue, and intensifies chronic pain, often leading to frustration, irritability, or guilt. These symptoms can also trigger or worsen anxiety and depression. These emotional changes then further amplify pain and disturb sleep, reinforcing the vicious cycle. He pointed out that even when the underlying disease goes into remission, changes in mood may persist. This is the case in Cushing’s syndrome, where many patients continue to report memory difficulties, trouble concentrating, irritability, and low stress tolerance.

When chronic pain, mood changes, and mental fatigue intersect, the consequences ripple through every area of life. Physically, pain-related fatigue makes exercise or even simple daily tasks challenging, leaving patients frustrated by their limitations. Socially and personally, low energy, anxiety, irritability, and emotional strain complicate relationships. This can lead to problems with partners (including intimacy issues), family members and friends, which can sometimes result in increased social isolation.

The impact on work life can also be significant. Fatigue, pain, and cognitive changes reduce productivity and jobs requiring memory and concentration become increasingly difficult. This often results in higher levels of absenteeism, sick leave, and in some cases, even permanent disability.

He concluded that chronic pain and poor sleep not only fuel anxiety and depression but also intensify physical and cognitive symptoms. It is for this reason that these interconnected aspects must be addressed as part of the overall treatment plan.

Many patients describe their pain as being misunderstood or minimized. How can healthcare professionals better address this topic, and what can patients do to improve communication?

When patients living with a pituitary or adrenal disorder feel that their debilitating symptoms of chronic pain or insomnia are being minimized by their healthcare provider, it can be very frustrating. Bridging this communication gap is the first step toward comprehensive care. Treatment is a two-way street: both the healthcare professional and the patient need to collaborate and actively participate in the therapeutic process. Building this partnership requires listening, empathy, and mutual trust.

Marc stressed that patients play an active and essential role in making sure their sleep problems and pain are included in their treatment plan. They should not hesitate to explain what they are experiencing. They should also not assume that the clinicians managing their pituitary or adrenal disorder fully understand how these symptoms affect their daily lives.

To better support this communication, he suggested the following to patients:

1. Document your symptoms
   Keep a brief record of pain frequency and intensity or of how well you sleep, as this helps make subjective symptoms more concrete. For example: “I wake up three times a night,” or, “The pain limits my activities three times a week” (see additional resources below for pain and sleep diaries).
2. Use quantifiable language.
   Turn your experience into numbers. For example: “On a scale of 1 to 10, my headache is a 7.” These simple scales help clinicians understand the severity and pattern of your symptoms

For healthcare professionals, the first essential step is to validate the patient’s experience. A practical way to do this is by incorporating standardized questionnaires and symptom scales during follow-up visits. These tools help identify the intensity, frequency, and duration of sleep problems or pain.

Additionally, the holistic nature of hormonal disorders means that timely referral to other specialists may also be necessary. This may include chronic pain units, sleep clinics, psychologists, physiotherapists, rheumatologists, orthopedists, or rehabilitation services. A coordinated, multidisciplinary approach is crucial so that the full burden of the disease and the complex interaction between hormones, brain, and body can be properly addressed.

Marc concluded by saying that empowering both patients and healthcare professionals with the right tools and information strengthens the therapeutic relationship and improves treatment adherence.

Aside from hormonal medication, what strategies or treatments have proven most effective in managing chronic pain and sleep issues in the long term?

Marc explained that this is a fundamental question that required a careful answer. He noted that treatment for pituitary and adrenal conditions is always based on the plan recommended by the referring endocrinologist. A multidisciplinary approach is often necessary, especially when patients experience intense and persistent symptoms such as sleep problems or chronic pain. Because these symptoms are so complex, each one requires a thorough assessment and specialized care.

He then shared several tips. He first noted that a good strategy for adjusting the biological clock may be to use techniques aimed at regulating the circadian rhythm, known as “sleep hygiene” techniques. These include:

• Creating a fixed routine: Try to go to bed and wake up at the same time every day, including weekends, to strengthen your internal clock.
• Treating your bedroom as a sanctuary: The environment should be dark, cool, and quiet so that the brain associates it solely with rest.
• Avoiding stimuli before bed: Reduce exposure to phones, tablets, and TV at least one hour before bedtime. The blue light interferes with the production of melatonin, the hormone that helps regulate the sleep-wake cycle and is vital for falling asleep.

Marc then moved on to chronic pain and fatigue. According to him, the most effective tools in this area are psycho-emotional and behavioral strategies, which help the brain to modulate how pain is perceived.

First, there is problem-focused coping, which encourages patients to ask themselves: “What can I do right now to improve my situation?” Shifting attention from frustration to practical solutions is linked to better emotional and physical well-being.

Secondly, he talked about the psychological concept called “Internal locus of control”, which essentially means believing that your actions and efforts, rather than external factors or luck, determine your outcomes. This can be applied to managing pain by performing small actions that reduce feelings of helplessness, such as adjusting posture, applying heat or cold to the area that hurts, or asking for help.

Finally, Marc emphasized the importance of social support. Emotional or informational support acts as a buffer against stress, and since chronic pain is influenced by the activation of the HPA axis, having support can ease both the physical and emotional impact.

These strategies can help patients regain control over their daily lives and complement the medical treatment recommended by their endocrinologist.

What advice would you give to patients living with chronic pain and/or sleep issues and to healthcare providers caring for these patients?

Marc started by sending a message of encouragement and empowerment to anyone living with chronic pain and sleep difficulties resulting from a hormonal disorder. He reminded patients that they are at the center of their recovery process and play an active role in coordinating and strengthening their own therapeutic progress.

What patients feel is not imagined, it is a biological consequence of the disease. However, mindset can also be therapeutic. Marc went on to explain the relationship between belief, attitude, and behavior. If you believe you can manage a symptom, your behaviors tend to be more active, such as seeking help or engaging in gentle exercise. Over time, this leads to better outcomes and he stressed that, “The goal is not only hormonal cure, but overall well-being.”

He then encouraged patients to be proactive in communication and not assume their doctors fully understand the impact of their pain or insomnia. He recommended that patients become the voice of their symptoms and use the tools discussed. Marc also insisted on the importance of caring for mental health, noting that psychological support and coping strategies are just as essential as hormone therapy. If needed, patients can be referred to a mental health professional for specialized care.

For healthcare professionals, Marc shared that the main challenge lies in integration and validation. He encouraged clinicians to start from the assumption that pain and sleep disturbances are direct symptoms of the pathology. Validating the patient’s subjective experience, he explained, is a cornerstone of long-term treatment adherence. He recommended that clinicians make use of standardized quality of life, pain and sleep scales during regular follow-ups. These tools transform subjective complaints into objective clinical data.

Finally, Marc stressed the importance of timely referrals when needed. Given the high burden of these conditions, doctors should not hesitate to involve pain specialists, sleep clinics, or psychologists to ensure truly comprehensive care. Ultimately, he concluded, “Improving the patient’s quality of life remains the most important measure of success.”

We would like to thank Marc Casas Boj for taking the time to share his experience and helpful advice about managing sleep issues and pain with us. We hope you enjoyed this year of WAPO Blogs and Vlogs and wish everyone a very happy and peaceful holiday season.

Additional Resources:

Articles

Mastering Sleep Hygiene: Your Path to Quality Sleep

The Neural Correlates of Pain and Sleep in Health and Disease

NORTHWEST Pain Guidance

Sleep apnea: Melmed, S., Casanueva, F. F., Klibanski, A., Bronstein, M. D., Chanson, P., Lamberts, S. W., Strasburger, C. J., Wass, J. A., & Giustina, A. (2013). A consensus on the diagnosis and treatment of acromegaly complications. Pituitary, 16(3), 294–302.

Mobile applications

Sleepio, the wellness app for managing sleep issues and insomnia

PainLog – Diario del Dolor

Sleep diaries

• Sleep and pain diary
• National Sleep Foundation’s Sleep diary
• Pain diary

In the latest edition of the 2025 WAPO Blogs and Vlogs series, we had the pleasure of interviewing Dr. Sandra Aleksic, an assistant professor of medicine in the divisions of endocrinology and geriatrics at the Albert Einstein College of Medicine in the Bronx, New York. In this interview, she explains how hormones change as we age, what aging means for people with pituitary disorders and what you can do to increase your longevity and quality of life.

This article provides a summary of the Vlog interview that you can find in English and Spanish on the WAPO website’s Library and YouTube channel.

How do hormone levels naturally change with aging?

Dr. Aleksic explained how hormone levels naturally shift as we age. In women, there is an abrupt drop in sex hormones around the age of 50. This marks the onset of menopause, when ovarian function declines, ovulation ceases, and menstruation stops altogether. At the same time, men tend to experience some decline in testosterone levels, but the drop is more gradual and is often tied to the man’s overall health. Interestingly, Dr. Aleksic noted that healthy men who live longer often maintain higher testosterone levels than their less healthy peers.

Another major hormonal shift involves growth hormone (GH) and insulin-like growth factor 1 (IGF-1). GH is necessary for growth and development and secretion peaks during childhood and adolescence, but starts to decline in our early twenties. While this reduction is a natural part of aging, it is one of the more dramatic decreases seen across our hormone systems and can be detected by measuring GH or IGF-1 levels.

There are also subtle changes in thyroid function as a person ages. It appears that older adults develop a state of slight hypothyroidism or reduced thyroid function, and some evidence suggests it may actually be a protective adaptation in aging. Antidiuretic hormone (ADH) levels tend to increase in older adults, and the body also becomes more sensitive to this hormone over time.

Lastly, Dr. Aleksic highlighted changes in the hypothalamic-pituitary-adrenal (HPA) axis, and specifically in the production of cortisol. While the total amount of cortisol does not decrease, there is a change in the circadian rhythm of cortisol production, meaning the normal daily cycle of how and when cortisol is released. In younger adults, cortisol levels are high in the morning and drop at night. In older adults, that nightly drop is less pronounced, and the entire cycle shifts earlier in the day.

Overall, hormonal changes with age are complex: some may contribute to the functional declines we associate with aging, while others could actually offer protective benefits.

Can you talk about hormone replacement therapy in older adults with pituitary disorders? Do treatment plans need to be adjusted as a patient ages?

Dr. Aleksic highlighted that naturally occurring changes in hormone levels with age influence how doctors approach treatment for older adults with pituitary hormone deficiencies (hypopituitarism).

In terms of presentation, older adults often have milder, less specific symptoms, which can lead to a delay in making the diagnosis of hypopituitarism. Common complaints like low energy, fatigue, changes in body fat distribution and loss of libido may be attributed to normal aging. Some of the hallmark signs seen in younger people, such as abnormal menstrual cycles in women, may no longer be present.Doctors must consider age-adjusted hormone levels, co-existing health conditions, and the effects of multiple medications, which can all contribute to making the diagnosis more challenging in older individuals.

When it comes to replacing hormones in older adults with hypopituitarism, both the natural hormone changes with age and any medications taken (which can affect how quickly these hormones are eliminated from the body and their effect) must be considered. Here are Dr. Aleksic’s recommendations:

• Glucocorticoids (for Adrenal Insufficiency): While there are no clear guidelines, expert opinion is to use lower doses, as hydrocortisone is cleared more slowly in older adults. Doctors should aim to administer the lowest possible dose of glucocorticoids needed to maintain energy levels while minimizing the risk of comorbidities, such as high blood pressure or elevated blood sugar.
• Thyroid Hormone: Replacement therapy is started with a lower dose and gradually increased. Older adults generally need less thyroid hormone because their bodies clear it more slowly than young adults. Over-replacement can increase the risk of osteoporosis, heart arrhythmias and heart failure, so target thyroid hormone levels in older adults are typically set lower than those for younger people.
• Growth Hormone: There is no clear one-size-fits-all guidance for continuing GH replacement in older adults. While GH naturally declines with age, some experts still recommend GH replacement for adults under 80 without any contraindications (e.g. active cancer). If given, it should be at a lower dose with careful monitoring of potential side effects such as increased blood pressure, elevated blood sugar, edema (swelling) and carpal tunnel syndrome.
• Sex Hormones (Women): Estrogen replacement is typically continued in women with hypopituitarism until the average age of menopause (around 50–51). After this point, treatment is usually tapered off, unless needed to manage symptoms like hot flashes.
• Testosterone (Men): Testosterone replacement can generally be continued in older men throughout life, although at lower doses and with age-appropriate hormone targets.
• Arginine vasopressin (AVP): Older adults tend to be more sensitive to AVP (or its synthetic analogue, desmopressin). The smallest dose necessary to avoid water retention or sodium imbalance is recommended. Treatment goals should also be realistic. While younger people do not usually wake up multiple times at night to urinate (unless they have AVP- deficiency), older adults may naturally wake up at night to urinate due to aging of the genitourinary system.

Across all hormone therapies, the general rule for older adults is to use the lowest effective dose and carefully monitor for any side effects. She reminded patients that hormonal regimens may have to be adjusted as you age. If your endocrinologist suggests lowering your dose of hormone replacement therapy, this is something to consider, as our needs for hormones do change as we age.

Is there any new research looking at hormones and aging that you would like to share with the pituitary community?

Dr. Aleksic shared findings from two very interesting studies.

• TRAVERSE Study

The TRAVERSE study looked at the cardiovascular safety of testosterone replacement in older men with hypogonadism and a high cardiovascular risk. Participants received either transdermal testosterone gel or a placebo, and were followed over several years to track cardiovascular outcomes.

Key findings:

• Testosterone replacement using transdermal gel did not raise the risk of cardiovascular events in this high-risk group of people, which is reassuring. The risk of several known complications of testosterone replacement therapy, such as elevated hemoglobin/hematocrit and prostate enlargement, were mitigated by careful dosing titration which maintained the average testosterone levels in the lower half of the reference range. However, it is unclear whether the same results would apply to other forms of testosterone replacement, such as injections, or higher doses of testosterone.
• There was an increased risk of blood clots, and the study also flagged newer concerns like acute kidney injury and atrial fibrillation, which need further investigation.

Although this study did not include patients with pituitary disorders, she concluded that testosterone replacement in older men with hypopituitarism can be considered, however transdermal application and lower doses (well below the mid-range of normal for young men) are recommended.

• ERCUSYN Study

This observational study, published in 2023, used data from the European Registry on Cushing’s Syndrome (ERCUSYN) to explore how the disease presents and is managed in adults aged 65 and older.

Key findings:

• About 10% of the 1800 people in the registry were over the age of 65, and 70% of them had pituitary-dependent Cushing’s syndrome (i.e. Cushing’s disease).
• In older adults, the sex distribution was nearly 50/50 (whereas it is predominantly female in younger groups). They were less likely to be overweight, more likely to report muscle weakness and skin symptoms that are associated with aging (rather than stretch marks seen in younger people), and less likely to mention depression or low libido.
• Pituitary tumors were larger in older adults, for reasons that remain unclear.
• Younger adults were more likely to undergo pituitary surgery as a first-line treatment. In older adults, medical therapy or radiotherapy was more common, likely due to increased surgical risks and comorbidities.
• Even when transsphenoidal surgery was successful, remission rates were slightly lower in older adults (about 50%) compared to younger patients (60–70%).

What health risks should older patients with pituitary disorders be mindful of and how can they manage symptoms that overlap with normal aging?

Dr. Aleksic shared that many pituitary disorders appear to accelerate age-related health issues, meaning that patients may experience conditions like cardiovascular disease, cancer, functional decline, muscle loss, and frailty earlier or more severely than others their age. The type of pituitary disorder can influence how these issues present in older adults.

In Cushing’s syndrome, for example, older adults present with more age-related symptoms such as high blood pressure, diabetes, or skin thinning. This differs from the typical features seen in younger patients. Loss of muscle mass, a concern in both aging and Cushing’s syndrome, appears even more pronounced in older adults with the condition. Treatment must not only control the underlying disease but also actively manage associated risks. Risks of cardiovascular disease and osteoporosis can be lowered through exercise, a healthy diet and medications. Bone-protective therapies (aimed at preventing fractures) like vitamin D, calcium, and anti-resorptive drugs should be provided as needed.

In acromegaly, older adults tend to experience more diabetes, hypertension, sleep apnea, and heart enlargement, compared to younger patients. While joint pain is common, data is lacking on whether there is a higher prevalence of osteoarthritis in older patients. Vertebral fractures, especially among postmenopausal women, are also observed, though it is unclear whether they are more frequent than in younger patients with acromegaly. There is some evidence suggesting higher rates of frailty and cognitive decline in older adults with acromegaly compared to their peers, but more research is needed.

What are the most important lifestyle changes that can help patients increase their longevity and quality of life as they age?

Dr. Aleksic emphasized that a larger number of older adults are now living with pituitary disorders. This is partly due to better treatment options leading to longer survival, and partly because of improved imaging techniques (like brain MRIs) that uncover incidental pituitary tumors.

Dr. Aleksic explained that when pituitary conditions are well-managed, older adults can focus on the same proven strategies for healthy aging as the general population. These include:

• Optimizing physical function

As we age, we tend to lose muscle mass and become more sedentary, which is detrimental to health. This can be even more pronounced in people with pituitary conditions like Cushing’s syndrome, where excess cortisol further accelerates muscle loss. Dr. Aleksic recommends a multifaceted exercise routine that includes aerobic, resistance, balance and flexibility exercises. This combination has been shown to extend life and improve overall health, and even small steps can make a meaningful difference.

• Reducing the risk of cardiovascular disease

Dr. Aleksic pointed out that cardiovascular disease remains the leading cause of death in older adults, including those with pituitary disorders. It is therefore important to be proactive in managing this risk through:

• Eating a healthy diet
• Maintaining a healthy body weight
• Taking medications as prescribed to lower cholesterol and manage blood pressure
• Monitoring blood sugar, in those with diabetes

• Not forgetting about our emotional and brain health

Dr. Aleksic reminded us not to overlook emotional well-being and brain health. Strategies that are essential for both include:

• Stress management
• Maintenance of strong social connections
• Getting enough quality sleep

She concluded by saying that in addition to treating the hormonal imbalances associated with pituitary disease, a holistic, age-sensitive approach is essential. It should focus on multiple prongs including exercise, diet, medications (to reduce risk factors), and emotional health.

We would like to thank Dr. Sandra Aleksic for taking the time to share her insights on this important topic. We hope that by following these recommendations, everyone can live longer, happier and healthier lives.

Additional resources:

Lincoff AM, Bhasin S, Flevaris P, Mitchell LM, Basaria S, Boden WE, Cunningham GR, Granger CB, Khera M, Thompson IM Jr, Wang Q, Wolski K, Davey D, Kalahasti V, Khan N, Miller MG, Snabes MC, Chan A, Dubcenco E, Li X, Yi T, Huang B, Pencina KM, Travison TG, Nissen SE; TRAVERSE Study Investigators. Cardiovascular Safety of Testosterone-Replacement Therapy. N Engl J Med. 2023 Jul 13;389(2):107-117. doi: 10.1056/NEJMoa2215025. Epub 2023 Jun 16. PMID: 37326322.

Amodru V, Ferriere A, Tabarin A, Castinetti F, Tsagarakis S, Toth M, Feelders RA, Webb SM, Reincke M, Netea-Maier R, Kastelan D, Elenkova A, Maiter D, Ragnarsson O, Santos A, Valassi E; and for the ERCUSYN Study Group. Cushing’s syndrome in the elderly: data from the European Registry on Cushing’s syndrome. Eur J Endocrinol. 2023 Apr 5;188(4):395-406. doi: 10.1093/ejendo/lvad008. PMID: 36749009.

Aleksic S, Bartke A, Milman S. “Endocrine Function in Aging”. Williams Textbook of Endocrinology, 15th edition, edited by Melmed S, Elsevier, Aug 2024.

Paragliola RM, Locantore P, Corsello SM, Salvatori R. Treating Hypopituitarism in the Over 65s: Review of Clinical Studies. Clin Interv Aging. 2023 Mar 21;18:423-439. doi: 10.2147/CIA.S370782. PMID: 36974195; PMCID: PMC10039666.

Ambrosio MR, Gagliardi I, Chiloiro S, Ferreira AG, Bondanelli M, Giampietro A, Bianchi A, Marinis L, Fleseriu M, Zatelli MC. Acromegaly in the elderly patients. Endocrine. 2020 Apr;68(1):16-31. doi: 10.1007/s12020-020-02206-7. Epub 2020 Feb 14. PMID: 32060689.

Gagliardi I, Chiloiro S, Vallillo M, Bondanelli M, Volpato S, Giampietro A, Bianchi A, De Marinis L, Zatelli MC, Ambrosio MR. Multidimensional geriatric evaluation in acromegaly: a comparative cross-sectional study. BMC Geriatr. 2021 Oct 26;21(1):598. doi: 10.1186/s12877-021-02549-4. PMID: 34702173; PMCID: PMC8547074.