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-CF counterparts. 

Varied social habits and behaviors between females and males also impact the differential 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.[4,12] Women often report, for instance, more significant concerns (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-CF counterparts.

Female Sex Hormones During the Menstrual Cycle

During the 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.[13] 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) studied the CF symptom-menstruation link, asking 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.[12,14] After initiating Trikafta™, females experienced decreased pulmonary symptoms overall. Still, they noticed a shift to gastrointestinal symptoms with hormonal fluctuations during the menstrual cycle.[12,14,15] 

Other researchers have noted the connection between pulmonary congestion and the menstrual cycle in CF. Coakley et al., for instance, suggest that for about one week of a 4-week menstrual cycle, women with CF seem to have a reduced ability to efficiently clear airway secretions.[16] According to Vidaillac et al., “the role of hormones as modulators of CF disease is further suggested by fluctuating lung function and nasal potential differences throughout a menstrual cycle.”[4] The authors assert that “further work dissecting out mechanisms through which sex steroids regulate host physiology and bacterial pathogenicity” is needed.[4]

Clinical studies have pointed to increased levels of estrogen as a primary 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 also thought to cause the conversion of P. aeruginosa to its more virulent mucoid form. The latter compromises lung function.[17] 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.[11] Further research is required to confirm this finding.

To understand the clinical changes seen in CF symptoms across the menstrual cycle, the typical patterns of changes in estrogen and progesterone need to be understood. At the start of menstruation (day 1), the levels of both estrogen and progesterone are low. Estrogen levels rise and peak as the follicle grows (follicular phase). Estrogen decreases dramatically with ovulation, while progesterone begins to increase. During the luteal phase (after ovulation), progesterone levels peak while estrogen begins to rise. Both hormones drop precipitously to start the monthly bleed.[2]

Figure 1: Hughan K, Daley T, Socorro Rayas M, Kelly A, Roe A. Female reproductive health in cystic fibrosis. Journal of Cystic Fibrosis. 2019;18:S96.

A review by Lam et al. describes the link between menstrual physiology and CF throughout the menstrual cycle. During menstruation, when the estrogen and progesterone levels are low, FEV₁ and FVC are also usually low. During the follicular phase, when estrogen levels peak and are at their highest, pseudomonas converts to its mucoid form, and pulmonary exacerbations increase.  During ovulation, airway inflammation peaks, the pseudomonas load increases, FEV₁ and FVC decrease, and pulmonary exacerbations are high.  During the luteal phase, when progesterone peaks and estrogen enjoys a smaller peak, inflammation decreases, FEV₁ and FVC return to the pre-menstrual baseline, and pseudomonas returns to its non-mucoid form.[2]

Estrogen increases secretion viscosity, increases mucin production, decreases chloride ion secretion, increases plugging, and decreases ciliary beat intensity, making it more difficult to clear the airways. Estrogen also increases viral immunity but decreases the immune response to bacteria and decreases bacterial clearing. Estrogen enhances the growth of pseudomonas and promotes the conversion to the mucoid form.[2]

Little is known about progesterone’s role in inflammation and infection in CF. In other conditions, progesterone decreases the immune response and decreases inflammation.  It reduces cellular lung damage, improves lung function after influenza infections, and may promote some immune defense memory in mouse models.[2]

Compared to the non-CF population, testosterone levels are no different in CF, but DHEA-S levels are lower. It is unclear what clinical outcomes low DHEA-S might produce, but low DHEA-S may be contributing to increased inflammation seen in females with CF.[2]

Figure 2: Lam G, Goodwin J, Wilcox P, Quon B. Sex disparities in cystic fibrosis: review on the effect of female sex hormones on lung pathophysiology and outcomes. European Respiratory Society Open Research. 2021;7:3.

Other Hormones Affecting Women with CF

Female Sex Hormonal Symptoms and Knowledge Gaps    

Researchers and women with CF are increasingly linking CF symptoms like fatigue, headaches, weight gain/loss, GI issues, depression, brain fog, or increased coughing to fluctuations in female sex hormones.[8,24] Some women, for instance, complain of monthly lung exacerbations that correspond with their menstrual cycles.[25] 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.[17] Some women have tried increasing the frequency of nebulizer treatments and airway clearance during the luteal phase to see if that prevents symptoms.[25] Besides pulmonary symptoms, GI symptoms may change with hormonal fluctuations during the menstrual cycle. Since cells lining the gastrointestinal tract have estrogen and progesterone receptors, these hormones may also affect women’s gastrointestinal function, including motility.[26] Adjusting a woman’s enzyme dose to respond to GI changes throughout the menstrual cycle may alleviate cyclic worsening of GI symptoms and absorption. However, this has not yet been studied in the CF population.[25] Without known effective therapies to treat the interaction of CF symptoms with hormonal fluctuations, these approaches may be an excellent place to begin management strategies. More studies are needed to discern if hormonal birth control, shifts in enzyme dosages, or other modalities are effective in reducing symptoms for the majority of women.

Changing sleep patterns and fatigue are essential 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 sleep patterns.[27] 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 well-being 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.[25] Which management strategies (medication, counseling, meditation, etc.) will be most helpful in relieving mental symptoms is unknown but worthy of serious inquiry. Due to the complexity of mental health management, these treatment approaches will likely need to be highly individualized for each patient. 

Menopause can bring with it many issues, including mood changes, heat and cold intolerance, night sweats, sleep disturbances, palpitations, joint pain, fatigue, cognitive decline, vaginal dryness, pain with intercourse, sexual dysfunction, and worsening CF symptoms. Menopausal symptoms often overlap or amplify preexisting CF-related symptoms.[19,28]  Wu et al. demonstrated that women with CF who took hormonal therapy had higher quality of life scores in physical functioning, vitality, treatment burden, role limitations, weight, respiratory symptoms, and digestion symptoms. Notably, all 26 women in this study were using a combination of estrogen and progesterone.[29] (See Menopause chapter).

Hormones & Mental Health

Some reports indicated that starting modulator therapy can exacerbate mental health issues such as depression and anxiety and create cognitive impairment. These symptoms generally can be alleviated with dose adjustments of either the modulator or the mental health medications.[30–32] Whether management of depression and anxiety through antidepressants and oral contraceptive pills (OCPs) can alleviate some of the side effects of modulators for females with CF remains a topic for future research. This approach has been studied as a way to manage premenstrual depression.[33] It remains to be seen if a similar treatment approach for the iatrogenic mood effects of modulators can be taken.

Psychosocial Aspects and Patient-Provider Trust  

Given the lack of definitive knowledge about female sex hormones and CF symptoms in the past, patients have had to press their providers to consider this connection. This dynamic may be based on scientific knowledge gaps and gender stereotypes. Such stereotypes can cause females to doubt their intuition about their bodies and can lead some providers to dismiss their observations. For example, some CFReSHC patient-partners reported that some providers questioned their hormonal symptoms and concerns. Others stated that their providers hesitated to believe them; they did not see questions about CF and hormones as valid.[13,25] 

The stigma surrounding the topic of hormones can prevent females with CF from discussing noticeable patterns with their CF providers or from asking questions about their menstrual periods. According to CFReSHC’s patient partners, females 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.[25] 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/their doctor fails to take the patient’s observations or questions seriously.

Females with CF view their CF team as their primary care providers and prefer to receive reproductive health counseling from their CF team and desire defragmented, coordinated care.[34,35] Participants in the study by Leech et al. voiced the concern that their reproductive health providers did not understand CF well enough to provide helpful care to a patient. One participant stated, “OB/GYNs don’t have enough knowledge of CF to really have a valuable input.”[35]

Another participant, in an article by Jain et al., reported: 

Sexual, reproductive, and general women’s health care has been largely ignored by my CF teams. In my experience, CF teams are rarely comfortable with topics such as birth control and pregnancy. I am always told to consult a primary care doctor or obstetrician, or gynecologist. These providers do not know enough about CF or the myriad of medications I take. They seem terrified to wade into the care of a woman with a chronic disease as complex as CF. Everything I have learned about safe and effective contraceptive options, pregnancy, and parenthood as a woman with CF has been acquired through my own research or by speaking with and listening to other women with CF. Until our caregivers can either collaborate or educate themselves on these issues, women with CF will continue to muddle through these topics, relying on each other to share our stories and give each other guidance and support.[6]

These issues put females with CF in the role of needing to self-advocate for comprehensive CF-informed hormonal care and to serve as the bridge that connects their disparate providers.