Hormones

Powerful chemical messengers impacting many functions within the body

CFReSHC CF-SRH Resource Guide by Patients for Providers and Patients

 

Introduction

Hormones are chemical messengers secreted by cells in the body, particularly endocrine glands, which include the pituitary, thyroid, and gonads (ovaries and testes).  They transmit messages through the bloodstream or lymphatic system which regulate many processes in different organs of the body. 

Female sex hormones:  Estrogen and progesterone influence a woman’s reproductive health, including menstruation, pregnancy, and menopause. Estrogen can also cause depression and headaches/migraines, can interfere with thyroid hormones, decrease libido, and impair blood sugar control. 

Estrogen is also associated with a pro-inflammatory state and, as such, may have attendant symptoms that are pertinent for women with CF [1]. Progesterone serves as an antidepressant, facilitates thyroid hormone action, restores libido, and regulates blood sugar levels. Testosterone may cause certain symptoms that interact with CF-related symptoms. In animal models, for example, researchers have seen testosterone decrease fluid and chloride secretions via CFTR (cystic fibrosis transmembrane conductance regulator). Estrogen does the exact opposite [2]. 

Estrogen exists in multiple forms throughout the lifespan: oestrone (E1) is predominant in menopause, oestradiol (E2) and oestriol (E3) are most abundant in perimenopause; estetrol (E4) is required for pregnancy. Not much is known about “the different oestrogens, their potency and subsequent metabolism” and how those factors may impact the health of women with CF [3]. We do know, however, that “all sex steroid hormone receptors have been shown to be expressed in lung tissue”[3]. Further, high levels of testosterone, coupled with low oestradiol and progesterone, in non-ovulating female CF patients potentially impact health outcomes [4]. Researchers have shown that estrogen and progesterone impact on: “CFTR mRNA expression, the tone of smooth muscle in the airways, airway responsiveness, the immune response, and exhaled nitric oxide (NO),” as well as changes in the cytology of the tracheobronchial epithelium during the menstrual cycle [5].  

Women with CF are not alone in female sex hormones impacting their disease. For their part, Tam et al. (2011) found that estrogen may modulate a variety of lung diseases, causing fluctuations in lung function in women with diseases like COPD, asthma, and CF that varies with their menstrual cycles [3,5]. Researchers do not find this change among women without lung conditions, signaling that circulating estradiol and progesterone may be involved in these pulmonary disease processes [5]. Interestingly, Tam et al. remark that, whereas the highest lung function for women with asthma occurs in the peri-menstrual period, female CF patients experience the highest lung function during the luteal phase and the lowest during the pre-ovulatory phase [3]. Johannesson concurs, finding that FEV1 was 66% of predicted in female CF patients during the luteal phase, while it was only 63% during ovulation, the latter of which is associated with increasing levels of estradiol [5]. Although a definitive mechanism is unknown, researchers believe that estradiol may increase mucin production in CF, compromising mucus clearance for female patients [3].

Priority Questions on Hormones for Providers and Patients to ask during Clinic Visit:

  • Have you noticed that your CF symptoms change as you go through your menstrual cycle?
  • Some women notice that their CF symptoms change depending on where they are in their cycle. Are you interested in tracking this for yourself to identify patterns? 
  • Are you aware of how your “female” sex hormones may change through your lifespan? Explain to the patient that there are shifts in hormones over the lifespan.

  • I use an application on my phone to track my CF and menstrual symptoms during my menstrual cycle.  Can you set aside some time today to discuss my findings? 
  • What kind of specialist should I see for hormonal issues? Can I get a referral? 
  • Do you have any expertise related to the interaction of CF and female sex hormones?
  • Report to your doctor if you notice if lung exacerbations or increased sinus congestion occurs cyclically.

Gender Disparities

Research has found that females experience more severe disease, poorer clinical outcomes, worsened lung function, and a survival disadvantage compared to their males counterparts across all age groups in CF [4,6].  While these researchers often explain the increased incidence and severity of airway disease in female patients as based upon differences between male and female anatomy, behavior, and hormones, they have not yet found a clear mechanism to explain the presence of sex disparities. Many hypothesize that estrogen may play a significant role [7]. In fact, many researchers believe that the increase in exacerbations in females with CF after the onset of puberty is a direct result of hormone fluctuations during the menstrual cycle [4,7,8]. They have shown that the most potent form of estrogen, 17β-estradiol, plays a prominent part in exacerbating lung function in CF females [9]. 

The Gender Gap and Women with CF’s Quality of Life 

According to the current knowledge about gender disparities and CF, women tend to have more severe disease progression, more exacerbations and higher mortality rates than their male counterparts [6]. Varied social habits and behaviors between females and males also impact the differential embodiment and progression of the disease. Females perceive their disease differently than males with CF, a fact that can influence their particular response to symptoms and their quality of life [4]. Women often report, for instance, greater concern (physical, social, and emotional) about their career, life expectancy, future success, and body image [4]. Women with CF often participate in fewer physical activities than males with CF, leading to inadequate airway clearance. As opposed to males with CF, some females limit their caloric intake to combat body image issues, an act that can contribute to nutritional deficiency [see Body Image chapter] [4]. As a result, women may feel as if they experience more exacerbations than men, when, in fact, their symptoms are typical CF symptoms. This assessment can negatively affect life activities like maintaining substantial gainful employment, negotiating family building stressors, and having difficulty fulfilling the same societal pressures expected of their non-CFcounterparts. 

Hormones during the menstrual cycle

During our CFReSHC Patient Task Force meeting on hormones, women with CF indicated that problems with female sex hormones were of great concern to them. They noticed that patterns of CF symptoms, like increased coughing and mucus production, correlate with their menstrual cycles. 

Researchers have made similar suggestions. Coakly et al., for instance, suggests that for about 1 week of a 4-week menstrual cycle, women with CF seem to have a reduced ability to efficiently clear airway secretions [20]. According to Vidaillac et al. “the role for hormones as modulators of CF disease is further suggested by fluctuating lung function and nasal potential differences over the course of a menstrual cycle”[4]. The authors also assert that “further work dissecting out mechanisms through which sex steroids regulate host physiology and bacterial pathogenicity” is needed [4]. 

Clinical studies also point to increased levels of estrogen as a main culprit for patterned CF symptoms. Not only do increased levels of estradiol correlate with more lung exacerbations during the follicular phase of the menstrual cycle, but they are thought to cause the conversion of P. aeruginosa to its more virulent mucoidy form. The latter compromises lung function [10]. In addition to showing evidence of such conversion, Chotirmall et al. analyzed data from the Cystic Fibrosis Registry of Ireland, finding that women who took oral contraceptive pills needed fewer antibiotics compared to those who did not take oral contraceptives [9].  Further research is needed to confirm this finding.

Indeed, many women with CF have connected their periods to pulmonary exacerbations but few studies have looked extensively at this issue. Godfrey and Sufian (co-founders of the CF Reproductive and Sexual Health Collaborative) are undertaking a CFF-funded pilot study (2020-2022) that asks participants to track their CF symptoms to see if there are indeed menstrually-related patterns, and to discern which symptoms most commonly occur among women.  

Graphic from Wikipedia user Isometrik

Hemoptysis and hormones

Catamenial hemoptysis is a condition that occurs when hemoptysis occurs with menstruation. It is a recognized clinical manifestation of thoracic endometriosis syndrome (TES) and is commonly treated with hormonal therapy [1]. While catamenial hemoptysis is considered rare in the general population, clinicians and patients have reported a connection between hormones, CF, and hemoptysis. 

Women with CF have reported hemoptysis during certain phases of their menstrual cycle. Extant literature indicates that hemoptysis affects men and women equally and that there are no discernable patterns in how and when it appears in CF patients (beyond age and lung deterioration). But CFReSHC patient-partners believe that further study on this particular issue is needed. A recent case report of a woman on Symdeko™ and then Trikafta™ published by Montemayor et al. suggests that when a female reports hemoptysis, providers need to gather a menstrual history because “a patient’s underlying clinical presentation and symptoms can be diagnostic of TES, and extensive diagnostic work-up may not be needed”[1]. Further, Montemayor remarks that women with CF who have catamenial hemoptysis and have a genetic mutation approved for Symdeko™ or Trikafta™ can be managed effectively with either of these CFTR modulators alongside hormonal contraceptive therapy [1]. Still, much more research on CF and catamenial hemoptysis is needed.  

Other Hormones affecting women with CF

THYROID

issues in women with CF have not been adequately explored in the medical literature. The thyroid impacts the basal metabolic rate and protein synthesis. It also regulates long bone growth (along with the growth hormone). Hyperthyroidism and hypothyroidism can negatively impact reproductive health by reducing rates of conception and raising the chances of early pregnancy loss. In a study looking at CF patients in Germany, Lutz Naehrlich et al. demonstrated high levels of iodine deficiency can lead to subclinical hypothyroidism. As such, some patients with CF may require iodine supplementation to assist with thyroid function [11].  

INSULIN

is an essential hormone produced by the pancreas to regulate blood sugar levels. Insulin, along with glucose metabolism, plays a role in fertility and other reproductive processes. Researchers in Denmark found that the prevalence of CFRD increases with age; it is also associated with chronic gram negative infection, poor lung function, and low BMI [12]. The study also found that “severe genotype, pancreatic insufficiency and female gender remain considerable intrinsic risk factors for early acquisition of CFRD”[12]. Overall, CFRD is associated with lung infections, lower lung function, and poor nutritional status, making “early diagnosis and aggressive treatment of CFRD more important than ever with increasing life span” [12]. 

GROWTH

hormone deficiency or delayed puberty was once considered a common problem in CF, however, recent reports now indicate that individuals with CF generally show normal development in puberty. Still, it remains important to evaluate pubertal development for “linear growth, bone mineral accrual, body image and psychosocial wellbeing,” all of which CF can influence [13]. Because researchers have found that “patients with poorly controlled diabetes and CF-related liver disease are predisposed to malnutrition and may be at higher risk of abnormal pubertal development,” they suggest clinicians evaluate the endocrine system to “avoid exacerbating potential problems such as poor body image, sub-optimal linear growth, and compromised peak bone mass” [13]. While the CF population experiences pubertal delay more often than the general population, comparative studies suggest that pubertal delay is linked to malnutrition rather than being an intrinsic feature of the disease. Since growth hormone stimulates pubertal growth and helps to regulate body composition, muscle and bone growth, as well as sugar and fat metabolism, recombinant growth hormone therapy can offer an effective way to improve the intermediate outcomes of height, weight, and lean tissue mass [13]. 

Hormonal Symptoms and Knowledge Gaps    

Researchers and females with CF are increasingly linking CF symptoms like fatigue, headaches, weight gain/loss, GI issues, depression, brain fog, or increased coughing to female sex hormones [6,14] Some women, for instance, complain of monthly lung exacerbations that correspond with their menstrual cycles [15]. In these cases, the provider may need to evaluate a patient’s observations further and offer creative therapeutic options. Some providers have begun to treat cyclical CF symptoms by prescribing birth control pills to see if they can help relieve pulmonary symptoms, as Chotirmall’s study suggests.10 For their part, some women have tried increasing the frequency of nebulizer treatments and airway clearance during the luteal phase to see if that obviates symptoms [15]. In addition to pulmonary symptoms, GI symptoms may also change with hormonal fluctuations during the menstrual cycle. Since cells lining the gastrointestinal tract have estrogen and progesterone receptors, it is possible these hormones also affect women’s gastrointestinal function, including motility [16]. Adjusting women’s enzyme dose as a response to GI changes throughout the menstrual cycle may relieve worsened GI symptoms/absorption, though this has not yet been studied in the CF population [15]. In the absence of known effective therapies to treat the interaction of CF symptoms with the hormonal fluctuations, these approaches may be a good place to start. More studies are needed to discern if BCPs, shifts in enzyme dosages, or other modalities are effective in reducing symptoms for the majority of women. 

Changing sleep patterns and fatigue are important manifestations of both physical and mental health, and can be related to CF, hormonal issues, or the intersection of both. However, it is difficult to discern if and when fatigue and sleep disruptions are caused by fluctuating female sex hormones, CF, or their interaction. Fatigue can affect a woman’s work and family obligations and can also affect her sleep patterns [17]. Sleep issues in CF, in turn, can negatively impact a woman’s adherence to her CF treatment routines. Addressing these symptoms, and their cyclical nature, is vital to ensure the health and wellbeing of women with CF. 

Hormonal changes not only affect physical symptoms but also mental ones. According to CFReSHC’s Patient Task Force, the interaction of hormonal fluctuations and CF can exacerbate feelings of anxiety and depression [15]. Management strategies (medication, counseling, meditation, etc.) most helpful in relieving mental symptoms is unknown but worthy of serious inquiry.  

Psychosocial Aspects and Patient-Provider Trust  

Given the lack of definitive knowledge around female sex hormones and CF symptoms, patients have, until recently, often had to press their provider to consider this connection. 

This dynamic may be based in a combination of knowledge gaps and gender stereotypes. Such stereotypes can cause females to doubt their own intuition about their bodies and can lead some providers to dismiss their observations. For example, some of CFReSHC patient-partners report that some providers have questioned their hormonal symptoms and concerns. Others state that their providers have hesitated to believe them; they did not see questions about CF and hormones as valid [15,19]. Stigma surrounding the topic of hormones can prevent women from discussing noticeable patterns with their providers or from asking questions pertaining to their menstrual periods. According to our patient-partners, women with CF might delay a gynecological appointment if their provider views such symptoms as only CF related, rather than the interaction of CF symptoms and the menstrual cycle. 

Moreover, a lack of knowledge, feelings of low self esteem, and having a low body image may prevent a female patient from seeking medical care or from inquiring about a noticed or changed symptom [15].  Menstrual periods and mood fluctuations can evoke shame and secrecy, causing women to downplay or avoid paying attention to cyclical health patterns. This stigma can be compounded if her doctor fails to take the patient’s observations or questions seriously.

Peer to Peer Advice

  • You may need to see a specialist beyond your CF provider to test or monitor your hormone levels. 
  • You can track your symptoms on a free period tracker app (even if you are not having a period) to show your provider any patterns that such tracking reveals.
  • Be your own advocate! Keep asking questions and seeking opinions from different providers.
  • Find an online group of women with CF, like those in CFReSHC, that you can talk to about your symptoms.
  • Listen to your body: get rest when you need it; inquire about a continuous glucose monitor if necessary.

Works Cited

  1. Montemayor K, Claudio AT, Carson S, Lechtzin N, Christianson MS, West NE. Unmasking catamenial hemoptysis in the era of CFTR modulator therapy. Journal of cystic fibrosis. 2020;19(4):e25-e27. https://search.datacite.org/works/10.1016/j.jcf.2020.01.005. doi: 10.1016/j.jcf.2020.01.005.
  2. Mohd Mokhtar H, Giribabu N, Kassim N, Muniandy S, Salleh N. Testosterone decreases fluid and chloride secretions in the uterus of adult female rats via down-regulating cystic fibrosis transmembrane regulator (CFTR) expression and functional activity. J Steroid Biochem Mol Biol. 2014;144 Pt B:361-372. doi: S0960-0760(14)00186-1 [pii].
  3. Tam A, Morrish D, Wadsworth S, Dorscheid D, Man SFP, Sin DD. The role of female hormones on lung function in chronic lung diseases. BMC women’s health. 2011;11(1):24. https://www.ncbi.nlm.nih.gov/pubmed/21639909. doi: 10.1186/1472-6874-11-24.
  4. Vidaillac C, Yong VFL, Jaggi TK, Soh ­M, Chotirmall SH. Gender differences in bronchiectasis: A real issue? Breathe. 2018;14(2):108-121. https://search.datacite.org/works/10.1183/20734735.000218. doi: 10.1183/20734735.000218.
  5. Johannesson M., Ludviksdottir D, Janson C. Lung function changes in relation to menstrual cycle in females with cystic fibrosis. Respiratory Medicine. 2000;94:1043-6. https://doi.org/10.1053/rmed.2000.0891. doi:10.1053/rmed.2000.0891.
  6. Harness-Brumley CL, Elliott AC, Rosenbluth DB, Raghavan D, Jain R. Gender differences in outcomes of patients with cystic fibrosis. Journal of Women’s Health (Larchmont, N.Y. 2002). 2014;23(12):112-1020. https://www.liebertpub.com/doi/abs/10.1089/jwh.2014.4985. doi: 10.1089/jwh.2014.4985.
  7. Zeitlin PL. Cystic fibrosis and estrogens: A perfect storm. The Journal of clinical investigation. 2008;118(12):3841-3844. https://www.ncbi.nlm.nih.gov/pubmed/19033654. doi: 10.1172/JCI37778.
  8. Sutton S, Rosenbluth D, Raghavan D, Zheng J, Jain R. Effects of puberty on cystic fibrosis related pulmonary exacerbations in women versus men. Pediatric Pulmonology. 2014;49(1):28-35. https://onlinelibrary.wiley.com/doi/abs/10.1002/ppul.22767. doi: 10.1002/ppul.22767.
  9. Saint-Criq V, Harvey BJ. Estrogen and the cystic fibrosis gender gap. Steroids. 2014;81:4-8. http://dx.doi.org/10.1016/j.steroids.2013.11.023. doi: 10.1016/j.steroids.2013.11.023.
  10. Chotirmall SH, Smith SG, Gunaratnam C, et al. Effect of estrogen on pseudomonas mucoidy and exacerbations in cystic fibrosis. The New England journal of medicine. 2012;366(21):1978-1986. https://search.datacite.org/works/10.1056/nejmoa1106126. doi: 10.1056/nejmoa1106126.
  11. Naehrlich L, Dörr H, Bagheri-Behrouzi A, Rauh M. Iodine deficiency and subclinical hypothyroidism are common in cystic fibrosis patients. Journal of Trace Elements in Medicine and Biology. 2013;27(2):122-125. http://dx.doi.org/10.1016/j.jtemb.2012.08.002. doi: 10.1016/j.jtemb.2012.08.002.
  12. Olesen HV, Drevinek P, Gulmans VA, et al. Cystic fibrosis related diabetes in europe: Prevalence, risk factors and outcome; olesen et al. Journal of cystic fibrosis. 2019;19(2):321-327. https://search.datacite.org/works/10.1016/j.jcf.2019.10.009. doi: 10.1016/j.jcf.2019.10.009.
  13. Goldsweig B, Kaminski B, Sidhaye A, Blackman SM, Kelly A. Puberty in cystic fibrosis. Journal of cystic fibrosis. 2019;18:S88-S94. https://search.datacite.org/works/10.1016/j.jcf.2019.08.013. doi: 10.1016/j.jcf.2019.08.013.
  14. Jain R, Sabanova V, Holtrop M, et al. Effects of sex hormones on markers of health in women with cystic fibrosis. Pediatric pulmonology. 2019:221.
  15. CF Reproductive and Sexual Health Collaborative. CFReSHC patient task force meeting on hormones. 4.29.2020.
  16. Hogan AM, Collins D, Baird AW, Winter DC. Estrogen and its role in gastrointestinal health and disease. International journal of colorectal disease. 2009;24(12):1367-1375. https://www.ncbi.nlm.nih.gov/pubmed/19655153. doi: 10.1007/s00384-009-0785-0.
  17. Han MK, Arteaga-Solis E, Blenis J, et al. Female sex and gender in lung/sleep health and disease: Increased understanding of basic biological, pathophysiological, and behavioral mechanisms leading to better health for female patients with lung disease. American Journal of Respiratory and Critical Care Medicine. 2018;198(7):850-858. https://doi.org/10.1164/rccm.201801-0168ws. doi: 10.1164/rccm.201801-0168ws.
  18. CF Reproductive and Sexual Health Collaborative. CFReSHC patient task force meeting on sexual function. 6.3.2020.
  19. CFReSHC Patient Task Force Meeting. Hormones and cystic fibrosis. 2.22.2018.
  20. Coakley RD, Sun H, Clunes LA, et al. 17β-estradiol inhibits Ca2+-dependent homeostasis of airway surface liquid volume in human cystic fibrosis airway epithelia. The Journal of clinical investigation. 2008;118(12):4025-4035. https://pubmed.ncbi.nlm.nih.gov/19033671/. doi: 10.1172/JCI33893.

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