Clinical and radiographic features of sarcoidosis in menopausal women – the impact on therapeutic approach and prognosis

Background/Aim. Sarcoidosis is a multisystemic granulomatous disease of unknown etiology. The aim of the study was to determine are there significant differences in clinical manifestations, radiographic and lung function findings and therapeutic approach in menopausal female sarcoidosis patients compared to premenopausal ones. Methods. Seventy seven Caucasian women (average age 43.71 years, range 38– 54) with sarcoidosis diagnosed at the University Hospital from January to October 2006, were included in the study. They were divided into two groups according to their menstrual period status. The group I included 42 women with normal menstrual cycle, while the group II included 35 menopausal women (either spontaneous or after hysterectomy). The patients were not under hormonal therapy. Results. We found significantly higher proportion of the first radiographic stage (66.7% vs 34.2%, p < 0.05) and acute form of sarcoidosis (57.2% vs 17.1%; p < 0.01) in the group I in relation to the group II. Extrapulmonary sarcoidosis was more frequent in the group II than in the group I (p < 0.01). Disturbances of lung ventilation were registered in 50.8% of all the patients, and decrease of one or both of diffusion parameters was found in 63.6%, but without significant differences between the groups (p > 0.05). Hypercalciuria was found in 19.1% of the patients in the group I and 42.8% of the patient in the group II (p < 0.05). A difference in the therapy approach was also found to be significant with methotrexate more frequently applied in the group II than in the group I (p < 0.01). Conclusion. Menopausal women with sarcoidosis may represent a group of patients that requires special attention in diagnostic procedure, therapeutic approach and follow-up, to prevent unfavourable course of the disease. Attention should be particularly focused on the detection of extrapulmonary sites involvement in this group of the patients. Further prospective studies are needed to reveal the role of hormones, and especially plasma estrogen level in sarcoidosis appearance.


Introduction
Sarcoidosis is a multisystemic granulomatous disease of unknown etiology.It usually involves mediastinal lymph nodes, pulmonary parenchyma, skin, eye, upper respiratory airways, bone marrow, liver, spleen and parotid gland, while kidney, nervous and osteomuscular systems and gastrointestinal tract are less frequently affected.In 90% of patients with pulmonary sarcoidosis, radiographic changes appear during the course of the disease 1 .Sarcoidosis has a favourable outcome in the majority of patients.Regression, either spontaneous or under therapy, occurs in 80% of patients.Erythema nodosum is the most frequent initial sign that could be seen in 15-34% of patients.It is often associated with bilateral hilar lymphadenopathy (BHL), which appoints to better prognosis 2 .
Although sarcoidosis may affect reproductive organs, it only rarely causes infertility.Irregular metrorrhagia due to endometrial and myometrial granulomatous changes is usual manifestation of this site involvement but, sometimes, early menopause may occur.In those women, symptoms seem to be numerous and multisystemic involvement is more frequent 3 .
Menopause denotes the last menstrual bleeding caused by the activity of ovary hormones on endometrium.Spontaneous, natural one can be evidenced by current hormonal status or retrospectively, after 12 successive amenorrhoic months.Perimenopause is a year before and a year after menopause.During this period, changes of the frequency and length of menstrual cycle occur, valungs appear, but still without amenorrhoic period of 12 months duration.Climacterium is a term related to involutive period of a 10-year duration (5 years before and 5 years after menopausal).Due to lack of estrogen, generalized atrophy of skin and mucosae occurs, together with osteoporosis, atrophy of urogenital tract and changes of cardiovascular system with increased risk of coronary artery disease 4,5 .This is why menopause presents a vulnerable period associated with the development of a variety of chronic and degenerative diseases or worsening of already existing ones.The aim of the study was to investigate if there were significant differences in clinical, radiographic and functional findings as well as therapeutic approach in menopausal female patients with sarcoidosis compared to those who had normal menstrual cycles.

Methods
The study group consisted of 77 Caucasian women aged 38-54 years (43.71, on average) who were diagnosed sarcoidosis and treated at the Institute of Lung Diseases and Tuberculosis of the Clinical Centre of Serbia in Belgrade (referral) and/or at the Department of Lung Diseases and Tuberculosis Kragujevac (regional facility) in the period from January to October 2006.We have retrospectively analyzed the data that were a part of routine diagnostic, therapeutic and follow-up procedures.Apart from the data on patient history and physical examination, we analyzed standard laboratory blood tests and paid a special regard to sarcoidosis activity markers such as serum angiotensin converting enzyme (sACE), serum and 24-hour urine calcium levels, and immunoglobulin E (IgE).Lung function tests and chest radiographs were carefully reviewed -we have used the International classification of sarcoidosis from 1981.The values of some additional tests were also estimated if done in particular cases.
The patients were divided into two groups according to their menstrual cycle status.The group I consisted of 42 women of the average age 43.17 years and regular period, while group II consisted of 35 menopausal women (either spontaneous or after hysterectomy) of the average age of 44.37 years.There was no significant difference in terms of age between the groups (t-test, p > 0.05).The patients were not under hormonal therapy.
The results were statistically analyzed by adequate methods of descriptive statistics, parametric statistics (t-test for two large independent samples) and non-parametric statistics (χ 2 -test, tables of contingence).

Results
Sarcoidosis had the acute onset in 24/42 (57.15%) cases in the group I, where five patients had chronic disease and relapse, while 40% of patients of the group II presented with subacute course of the disease (14/35).This highly significant difference is shown in Table 1 (p < 0.01).
The first stage of the disease was found in 40/77 patients (51.95%) and 28 (66.67%) of them belonged to the group I.In the majority of patients of the group II, radiographic signs of the second stage were found (15/35; 42.86%) compared to 34.28% of the first stage.We found significant differences in frequency of particular stages of the disease between the two groups as shown in Table 2 (p < 0.05).
Initial symptoms and signs of acute sarcoidosis such as disturbed general condition, febrile temperature, weakness and fatigue followed by polyarthralgia, dominated among patients of the group I (p < 0.05).The most frequent respiratory symptom found was dry cough (36.36%) while only 7.79% of the patients complained of expectoration.We found hemoptysis as initial sign in one case (Table 3).Thirty patients (38.95%) presented with dyspnea (21 of them experienced it in rest), while chest pain and feeling of retrosternal pressure was found in 16 (20.87%) of them.The frequencies of these symptoms have not significantly differed between the groups (p > 0.05).Eighteen (23.37%) of the patients had no general or respiratory symptoms at all, and they were diagnosed sarcoidosis during systematic check ups or clinical investigations on the occasion of symptoms of other organs such as skin lesions or abnormal laboratory findings.The difference was not significant (p > 0.05).
Pulmonary involvement without evidence of extrapulmonary sarcoidosis was found in 11 of the patients -10 in the group I and one in the group II (p < 0.01).Arthritic involvement and erythema nodosum were more frequent in the group I, while specific skin lesions and changes in parenchymal organs were more frequently found in the group II (p > 0.05).The sites of extrapulmonary sarcoidosis are shown in Table 4.In the majority of the patients (53/77; 68.33%) physical findings were normal as well as the findings in particular groups (group I: 76.19%; group II: 60%; p > 0.05).
Lung function tests were normal in almost half of the patients (49.36%) when it comes to spirometry parametres.Eleven (14.28%) of the patients had obstructive ventilation disturbance, and the most frequent finding was decreased forced expiratory flow of the small ventilation pathways registered in 19 patients.In this term, no difference between the groups was found.Values of tansfer factor and diffusion coefficient for carbon monoxide single breath (DCOSB) were within normal limits in 28 (36.36%) of the patients.Abnormal values of both diffusing capacity lung transfer factor/coefficient of diffusion (D/VA) and DCOSB were found in 49.36%, while in eight (10.39%)only DCOSB, and in three (3.89%)D/VA decrease was registered (p > 0.05).Four patients of the group II had gas exchange disturbances and two of them suffered from partial respiratory insufficiency.
We found significantly different frequency in 24-hour urine calcium levels: 23 (29.87%) in the group I and 14 (42.86%) in the group II (p < 0.05).Increased levels of sACE were found in 23 (29.87%) of the patients with similar frequencies of the finding in both groups (p > 0.05).Equal numbers of patients in each of the groups had decreased sIgE levels -32 (41.56%) patients in total.
The therapeutic approach consisted of follow-up of spontaneous remission in 11 patients (14.28%); application of methylprednisolon orally in 43 (55.84%)patients with majority of them in the group I, and in 23 (29.88%) patients methotrexate was needed to achieve satisfactory regression (the vast majority of them belonged to the group II).The details and significance of the differences found are shown in the Table 5.

Discussion
The results of our study showed important differences in several variables observed between the two groups of patients but also a few similarities.About half of our patients were in the first evolutive stage of sarcoidosis and this stage was more frequent in the patients with regular period (66.67%).The average age of menopausal women in the western world is 51 years (range 39-59) 6 .The participants in our study were of similar age range (38-54 years).We have included only one woman with sarcoidosis with early menopause in the age of 38 years, while the other woman had a regular period in her age of 54 when sarcoidosis was diagnosed.
Acute onset of the disease, registered in 38.96% of the cases, was most frequently associated with impaired general condition and polyarthralgia, and the majority of the women belonged to the premenopausal group.We found one or more symptoms or signs of impaired general condition in 92.86% and 71.33% women both in the group I and the group II, respectively; the difference was significant.Febrile temperature, weakness and malaise were most frequently present.We found sweating in not more than 16/77 patients, although vasomotor disturbances have been known as frequent in climacteric having been reported in 4/10 women older than 40 years 7 .However, respiratory symptoms frequency has not differed between our premenopausal and menopausal patients.
Sarcoidosis usually has a favourable diseases outcome, especially in younger women with acute onset, erythema nodosum and polyarthralgia.As the first sign of the disease, erythema nodosum could be found in 15-34% of sarcoidosis patients, especially those in generative period, and in women during pregnancy or lactation, appointing to hormonal activity as a possible etiological cofactor 8,9 .Not rarely, it is associated with radiographic finding of BHL, and, if there is no evidence of extrapulmonary involvement, therapy is not necessary.In the majority of the cases, relapses do not occur even without treatment.
Sarcoidosis mortality is generally low except for Scandinavian countries.Causes of the lethal outcome are usually extrapulmonary site involvement such as myocardial and central nervous system sarcoidosis as well as renal insufficiency due to nephrocalcinosis and respiratory insufficiency accompanied by chronic cor pulmonale.Pulmonary complications (pneumothorax, embolism, aspergillosis) appear less frequently 10 .Extrapulmonary sites affected in our patients included myocardium in eight cases (in two of them also pericardium was affected), and kidney in 12 cases.We did not find neurosarcoidosis in a single patient.
Specific skin lesions, which represent a bad prognostic sign, were found in 33 patients and 18 of them were menopausal (group II).In the course of climacteric, atrophy of both skin and mucosa appear and that is why a variety of sensations like tongue burning, dry mouth, taste changes, decreased tears production, etc. may occur.Similar symptoms could be seen in sarcoidosis due to involvement of salivary and tear glands 11 .
We found skeletal lesions in 28.67% menopausal women (group II) and in 11.90% in the group with a still normal menstrual cycle.A certain number of healthy women complain of small joints pain or periarthricular pain during pre-or postmenopausal period.Both physical and radiographic examinations are not good enough to reveal any pathological process in bones and/or joints 12,13 .Musculoskeletal system is affected in a third of sarcoidosis patients and the changes are most frequently located in phalangae of the hands and feet, foot joint, elbow, knee, and rarely in skull, illium, ribs or sternum.Cystic changes predominate, rarely osteolytic lesions appear, or, sometimes, a loss of trabecular structure may be found.All these lesions are usually asymptomatic.When the process develops to synovitis, signs of arthritis appear, and the process usually affects larger joints 5 .In 30-50% of sarcoidosis patients painless muscular granulomas are present, while symptomatic muscular lesions are very rare.However, when symptomatic, they could be found more often in women and may represent the only manifestation of the disease 14 .
Lung function testing in sarcoidosis is very important, especially in patients with parenchymal lesions.Apart from basic spirometry, it includes measuring of lung diffusing capacity, lung compliance and respiratory gas analysis.Vital capacity decrease, which indicates restrictive pattern of ventilation disturbance, represents the first functional impairment described in sarcoidosis.Although it has been known for a long time that disturbances of diffusion and ventilation obstruction (first of all in small respiratory pathways) were more frequent, sarcoidosis is still categorized into the group of restrictive pulmonary diseases [15][16][17] .Bronchial obstruction may be a consequence of endobronchial lesions, seen in 50% of sarcoidosis patients in the stage I of the disease, and also a sign of bronchial hyperreactivity, evidenced in sarcoidosis patients -non smokers with changes in bronchial mucosa 18,19 .Lung function testing in our patients has not revealed significant difference in terms of frequency, type or severity of ventilation disturbances.Measuring of transfer factor is important step since impairment of diffusion is the most frequent functional disturbance in sarcoidosis.In these patients, decreased diffusion coefficient is registered more frequently than lung transfer factor 20 .We found abnormal values of diffusion parameters in 63.64% of the patients but without significant difference between menopausal and premenopausal women.
Dynamics of the disease, remissions, exacerbations, as well as response to therapy could be all better assessed by following up the level of markers of sarcoidosis activity.Hypercalcaemia and hypercalciuria are considered pathognomonic for sarcoidosis.They appear as a consequence of increased level of active metabolite of vitamin-D 3 , calcipherol, or 1.25 dihydroxy-D 3 generated extrarenally.That is why hypercalciuria may also occur in other granulomatous diseases and in sarcoid-like syndromes.Increased level of 1.25(OH) 2 -D 3 may cause marked somnolence, fatigue and other symptoms such as pain in joints and muscles, and appearance of respiratory symptoms.Patients that suffer from sarcoidosis may have significantly increased levels of 1.25(OH) 2 -D 3 during summer months.That is the major reason for their frequent complains presented by skin manifestations and polyarthralgia during summer 21,22 .
Levels of sACE are reported to be increased in 50-80% of sarcoidosis patients.Due to its presence on the surface of endothelial capillary cells and macrophages of the epitheloid granulomas, high sACE concentrations are found most frequently in the patients with intrathoracic sarcoidosis 9 .A positive correlation has been proved between sACE level and radiographic presentation of the degree of sarcoidosis extensiveness but this correlation existed only in disseminated forms of the disease.Increased sACE levels also correlated well with hypercalcaemia and hypercalciuria 23 .
Estimation both of prognosis and decision on therapy approach or leaving a patient on spontaneous regression and follow-up, always include careful evaluation of clinical, radiographic and biochemical findings together with markers of sarcoidosis activity.Lung function tests are very important in this process, as well 24 .Importance of measuring level of IgE in order to predict prognosis of the disease has been particularly highlighted during recent years since low IgE level may speak in favor of chronic course of the disease.We found lower IgE levels in the same proportion of the cases in both the analyzed groups.
Indicators of favorable prognosis and possibilities of spontaneous remission are: clinical criteria, which include typical clinical presentation of acute sarcoidosis, first of all the appearance of erythema nodosum, polyarthralgia and general symptoms; radiographic criteria, which include a finding of symmetric BHL and pulmonary involvement only, i.e. without an evidence of dissemination that lead to extrapulmonary disease; normal lung function and normal values of markers of sarcoidosis.With regard to the latter, we would like to highlight again the importance of measuring lung transfer factor because standard spirometry gives an estimation of pulmonary function based on anatomical lung volumes.It does not give an estimation of physiological function which may be affected by fibrosis.
Therapy for sarcoidosis is empirical.It is usually based on systemic corticosteroids, which are effective for granulomatous changes, including endobronchial ones, and their immunologic and metabolic products.It is initiated when systemic symptoms or pulmonary function deterioration occur.Disadvantage of this therapy is lack of full effect on fibrous pulmonary lesions 25 .
In our study, prednisone was administered in a dose of 40 mg/daily in the initial phase, in the majority of the patients.Our decision to start immunosuppressive therapy was based on the presence of BHL and extrapulmonary manifestations; radiographic presentation of stage II or III, or atypical stage I of the disease; lung function disturbance; increased biochemical markers of sarcoidosis activity; chronic course or relapse of the disease.
The following studies show concordant approach: a twoyear follow-up has shown that spontaneous remission appeared in patients with slight impairment of lung function and discrete symptoms of the disease; radiographic progression together with appearance of numerous symptoms and functional disturbances required starting the therapy, most frequently corticosteroid; immediate treatment of pulmonary stage II(-III) sarcoidosis, but not stage I disease has improved a 5-year prognosis with regard to lung function variables in a randomized, double-blind, placebo-controlled, parallel-group study [26][27][28][29] .Milošković V, et al.Vojnosanit Pregl 2010; 67(1): 13-18.
In the case of corticoresistance or contraindications for administering corticosteroids, synthetic antimalarics and cytostatics are recommended, most frequently methotrexate 30,31 .
Incidence rate of sarcoidosis in our local settings is about 1.8/100.000population 32 .However, the fact that diagnostic procedure, treatment and follow up in our study group were performed in the national referral and regional facilities, made it possible to obtain a sufficient number of patients together with all the relevant parametres needed to meet the primary objectives of the study.On the other hand, being a retrospective one, our study has limitations and one of them is a lack of possibility to include some additional parameters, which were not a part of routine practice like hormonal level investigation.The results of our study indicate that it might be important to reveal a possible role of estro-gen plasma level in sarcoidosis appearance and its influence on the course of the disease.

Conclusion
Menopausal women represent a group of patients that require more attention not only in diagnostic procedures for sarcoidosis, which should be particularly focused on possible extrapulmonary sites involvement and their complications, but also in terms of therapy and follow-up.Adequate initial treatment may lead to improvement of lung function, better prognosis, and prevention of unfavourable course of the disease and, thus, quality of life improvement.The results of our study suggest that more studies are needed to reveal the significance of estrogen and other hormonal influences in sarcoidosis development and the course of the disease.

Table 2 Stage of sarcoidosis in nonmenopausal (group I) and menopausal (group II) women
*p < 0.05, group I vs group II (χ² test)

Table 3 Symptoms and signs of sarcoidosis in nonmenopausal (group I) and menopausal (group II) women
*p <

Table 5 Therapy of sarcoidosis in non menopausal (group I) and menopausal (group II) women
*p < 0.01, group I vs group II (χ² test)