Clinical Rheumatology https://doi.org/10.1007/s10067-020-05522-5

ORIGINAL ARTICLE

Prevalence and clinical associations with premature ovarian insufficiency, early , and low ovarian reserve in systemic sclerosis

Arporn Jutiviboonsuk1 & Lingling Salang2 & Nuntasiri Eamudomkarn2 & Ajanee Mahakkanukrauh1 & Siraphop Suwannaroj1 & Chingching Foocharoen1

Received: 9 October 2020 /Revised: 5 November 2020 /Accepted: 23 November 2020 # International League of Associations for Rheumatology (ILAR) 2020

Abstract The low prevalence of in women with systemic sclerosis (SSc) is due to multi-factorial causes, including premature ovarian insufficiency (POI). The study aimed to determine the prevalence of POI, early menopausal status, and any clinical associations of these among Thai female SSc patients. An analytical cross-sectional study was conducted among female SSc patients between 18 and 45 years of age. The eligible patients underwent blood testing for follicle stimulating hormone and anti- mullerian hormone levels, gynecologic examination, and transvaginal ultrasound for antral follicle count. We excluded patients having surgical amenorrhea, previous radiation, and history of hormonal contraception < 12 weeks and pregnancy. A total of 31 patients were included. The majority (67.7%) had diffuse cutaneous systemic sclerosis. Three patients were POI with a preva- lence of 9.7%. The factors associated with POI were a high cumulative dose of cyclophosphamide (CYC) (p =0.02)andthelong duration of CYC used (p = 0.02). After excluding POI, early menopause was detected in 10 patients with a prevalence of 35.7%. The factors associated with early menopause were long disease duration (p = 0.02), high cumulative dose of CYC (p =0.03),and high cumulative dose of prednisolone (p = 0.02). Low ovarian reserve according to POSEIDON definition was found in 28 patients with the prevalence of 90.3%. POI in Thai SSc was uncommon, whereas early menopause and low ovarian reserve were frequently revealed. A high cumulative dose of CYC was associated with both POI and early menopause. Physicians should be aware of reproductive outcomes and advise patients at risk.

Key Points • POI is revealed in patients with SSc particularly in who received high cumulative dose of cyclophosphamide, while early menopause and low ovarian reserve were major reproductive problem among SSc. • Prescriptions for CYC for female SSc—both for young patients of reproductive age and premenopausal middle-aged women—should be concerned of the long-term effects on gonadal function.

Keywords Early menopause . Immunosuppressant . Premature ovarian insufficiency . Reproduction . Systemic sclerosis

* Chingching Foocharoen Ajanee Mahakkanukrauh [email protected] [email protected]

Arporn Jutiviboonsuk Siraphop Suwannaroj [email protected] [email protected] Lingling Salang 1 [email protected] Department of Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand Nuntasiri Eamudomkarn 2 Department of Obstetrics-Gynecology, Faculty of Medicine, Khon [email protected] Kaen University, Khon Kaen 40002, Thailand Clin Rheumatol

Introduction The current study aimed to determine the prevalence of POI, early menopausal status, and ovarian reserve function Systemic sclerosis (SSc) is a rare multisystem and predomi- and the clinical associations for each among Thai female nantly affects women, such that the female to male ratio SSc patients. The assessment will benefit families planning ranges between 3:1 and 14:1 and the mean age at onset is the course of treatment. 45 ± 15 years [1]. Although the onset of disease is most com- mon among middle-agers, presentation among those of repro- ductive age does occur [2–4]. Pregnancy has been reported in Method SSc patients, but the prevalence is low [5]. The cause of the low prevalence of pregnancy in SSc is uncertain. It could be An analytical cross-sectional study was conducted among late age at onset of SSc, sexual dysfunction, unwillingness to Thai, adult, SSc, and female patients between 18 and 45 years have children, premature ovarian insufficiency (POI), and/or of age seen at the Scleroderma Clinic, Srinagarind Hospital, low ovarian reserve associated with increased age. Khon Kaen University between May 2019 and March 2020. POI is the term used to define women under 40 years of age Blood samples were drawn from all eligible patients on the who present with amenorrhea lasting more than three cycles or day of enrollment and 4 weeks after that to assess the levels of 4 to 6 months and a hypoestrogenic-hypergonadotropic serum FSH and AMH. Each patient underwent a gynecologic exam- profile (follicle stimulating hormone (FSH) levels ≥ 40 mIU/ ination and evaluation of the genital tract for any abnormali- mL on two occasions apart) [6, 7]. Antral follicle count (AFC) ties and a transvaginal ultrasound to evaluate the AFC. Two and serum anti-mullerian hormone (AMH) can be used as a experienced gynecologists performed the transvaginal ultra- marker for residual ovarian reserve, which represents poor sound. We excluded patients having surgical amenorrhea, pre- fertility and is predictive of the individual response to ovarian vious radiation, history of hormonal contraception less than stimulation in in vitro fertilization (IVF) [8]. AMH is pro- 12 weeks ago, implant contraception, hormonal IUD, and duced by granulosa cells of the primary follicles, which re- pregnant patients. flects the continuous decrease in the pool of and fol- licles during life [9]. AFC is a marker representing the total Operational definition number of antral follicles in both , as observed by transvaginal ultrasound [10]. Diagnosis of SSc was based on the 1980 American Rheumatism Women with POI also have diminished general and sexual Association classification criteria of SSc [23]or2013ACR/ well-being and have more psychological problems [11]. The EULAR Classification Criteria for Scleroderma [24]. The SSc prevalence of POI is approximately 1% of women under 40 years subset was classified into dcSSc or lcSSc according to LeRoy [12, 13], and spontaneous early menopause is reported to affect et al. [25]. Onset of SSc was defined as the time of first non- approximately 5% of women between 40 and 45 [14]. POI is Raynaud SSc symptom as reported by the patient. frequently idiopathic, possibly due to genetic causes, enzyme In women under 40 years of age, premature ovarian insuffi- deficiencies, infections, metabolic syndromes, and/or autoim- ciency (POI) was defined by triads of amenorrhea for at least 3 mune diseases [7]. The prevalence of autoimmune disease report- cycles or 6 months and elevated FSH serum concentrations over ed in POI varies between 10 and 55% [15]. In 1995, observa- 40 IU/L in two samples at least 1 month apart [26]. Early men- tional data on genital tract abnormalities and sexual function opause was defined as having a final menstrual period between impairment thereof in SSc indicate that 2 of 60 patients had early 40 and 45 years of age [27]. The low ovarian reserve test was menopause (one age 29 and one 38) [16], or 3.3% of the sample. measured using AMH or AFC. POSEIDON is the acronym for In 2005 and 2017, two cases of POI were reported in a 25- and the Patient-Oriented Strategies Encompassing Individualize D 31-year-old SSc patient, respectively [17][18]. Number. The POSEIDON criteria for stratification of Recent studies on patients with diffuse cutaneous SSc low prognosis patients in assisted reproductive technology (dcSSc) indicate that postmenopausal—rather than premeno- (ART) [28] were (a) low serum AMH under 1.2 ng/mL and pausal status—is associated with a lower mean modified (b) less than 5 follicles from both ovaries as identified by Rodnan skin score but that this effect was smaller than in transvaginal ultrasound. Pulmonary arterial hypertension (PAH) limited cutaneous SSc (lcSSc) [19]. In contrast to the skin, is defined by a mean pulmonary arterial pressure > 20 mmHg postmenopausal status increased the risk of developing pul- confirmed by right heart catheterization [29]. Interstitial lung was monary hypertension [20] and is associated with low BMD considered present when interstitial fibrosis was detected by ei- and osteoporosis [21]. Early menopause, moreover, is associ- ther chest radiographic or HRCT. The definition of esophageal ated with lower bone mineral density [22]. To date, there has involvement was fulfilled when any esophageal symptoms of been no study of ovarian function in SSc patients, particularly SSc were revealed (i.e., esophageal dysphagia, heartburn, or re- vis-à-vis the prevalence of POI and low ovarian reserve, and flux symptoms). Stomach involvement included dyspepsia, early the clinical association of POI. satiety, and bloating [30]. Oral CYC was applied for treatment Clin Rheumatol instead of intravenous CYC among our SSc patients since 2012 Since there was a low number of events (i.e., CYC used in [31] due to difficult venous access; hence, CYC in our study was patients without POI), a multivariate analysis was not avail- referred to oral CYC. able due to statistical limitations.

Statistical analysis Prevalence and clinical associations with early menopause in SSc The prevalence of POI in SSc patients was investigated with its 95% CI. Percentages and proportions were calculated for the After we completed the analysis while excluding POI, early categorical data. Mean with SD or median with interquartile menopause was detected in 10 cases with a prevalence of range was calculated for continuous data as appropriate. 35.7% (95% CI 18.6–55.9). After comparing the clinical char- Categorical data were analyzed using the chi-square or Fisher acteristics between SSc with and without early menopause, we exact test as appropriate. Continuous data were analyzed using found that the mean age of patients with early menopause was the Student t test or Mann-Whitney U test as appropriate. p values significantly higher than in those without early menopause under 0.05 were considered statistically significant. Data analy- (43.6 ± 1.5 years vs. 37 ± 6.6 years, p = 0.004). The SSc with ses were performed using STATA version 16.0 (StataCorp., early menopause had a (a) longer disease duration, (b) higher College Station, TX, USA). cumulative dose of CYC used, (c) longer duration of CYC The study was designed by the authors and approved by the used, (d) younger age starting CYC, (e) higher cumulative Human Research Ethics Committee of Khon Kaen University as dose of prednisolone used, and (f) younger age starting steroid per the Helsinki Declaration and the Good Clinical Practice than patients without early menopause (p = 0.02, 0.03, 0.03, Guidelines (HE621005). All eligible patients signed informed 0.01, 0.02, and 0.01, respectively) (Table 3). We did not, consent before enrollment. The sponsor had no role in the study. however, do a multivariate analysis to determine the final model of factors associated with early menopause because of the low number of events. Results Genital abnormality and fertility status in SSc patients Patient characteristics Twenty-six of the patients consented to a gynecological ex- A total of 31 patients were included in the study. The mean amination and transvaginal ultrasound. Of these, 5 (19.2%) age on the study date was 39.1 ± 6.3 years. The majority had vaginal atrophies and 4 (15.4%) vaginal dryness. The (67.7%) was dcSSc subset, and 71.4% of overall patients patients with vaginal atrophies and vaginal dryness were older had positive for anti-topoisomerase I antibody. The mean dis- and more frequent being dcSSc than those who had no vaginal ease duration was 9.7 ± 7.5 years. Half of the patients (55.6%) atrophies and vaginal dryness, but there were no statistical had interstitial lung disease, and these patients received glu- significance (data not shown). All of the patients had a normal cocorticoids and immunosuppressive agents, including cyclo- Pap smear. One case had a small-sized uterus (3.1 cm in the phosphamide (CYC). sagittal plane and 2.0 cm in the anteroposterior plain by transvaginal ultrasound evaluation), and 8 cases (30.8%) had Prevalence and clinical associations with POI in SSc ovarian cyst(s) (7 were normal functional cysts, and 1 was a bilateral ovarian endometrioma). Menopausal symptoms were POI was revealed in 3 cases with a prevalence of 9.7% (95% CI reported from 7 cases (26.9%) (2 in patients with POI and 5 2.0–25.8). After comparing the clinical characteristic between with early menopause). Dyspareunia was reported in 4 cases SSc with and without POI, we found that the median cumulative (15.4%) (2 with POI and 2 with early menopause). dose of CYC in POI patients was significantly higher than that in According to the POSEIDON definition of a patient with a patients without POI (37.1 g (IQR 13–38.3) vs. 0 g (IQR 0– poor prognosis undergoing ART, 28 of 31 patients had low 13.4), p = 0.02). The median duration of CYC used in the POI ovarian reserve (prevalence = 90.3%; 95% CI 74.2–97.9). The group was significantly longer (660 days (IQR 365–960) vs. median AMH among the SSc patients was 0.035 ng/mL (IQR 0days(IQR0–300), p = 0.02), and the starting age of cyclophos- 0.01–0.27). The mean age of the patients with a low ovarian phamide use was younger in the POI group (27 years (IQR 19– reserve was higher than among the patients with a normal 33) vs. 37 years (35–38.5), p = 0.02). There was no significant ovarian reserve (40.4 ± 5.1 years vs. 27.5 ± 4.5 years, p = difference with respect to the demographic data, clinical charac- 0.0003). One patient had a low ovarian reserve: she was teristics, serology, or prednisolone prescription between the two 21 years old with normal menstruation and no menopausal groups (Table 1). The clinical details of the patients with POI are symptoms. She had dcSSc and received mycophenolate mo- presented in Table 2. fetil for less than 2 years. Obstetric history among patients Clin Rheumatol

Table 1 Clinical association with POI

Characteristic Overall POI No POI p value N =31 N =3 N =28

Demographic - Age (years); mean ± SD 39.1 ± 6.3 35.2 ± 4.2 39.5 ± 6.4 0.27 - BMI (kg/m2); median (IQR) 20.1 (17.9–22.7) 17.1 (15–18.4) 20.7 (18.8–23.3) 0.08 - Dyslipidemia (%) 4 (12.9) 1 (33.3) 3 (10.7) 0.35 - Hypothyroidism (%) 1 (3.2) 1 (33.3) 0 (0) 0.09 - Hyperthyroidism (%) 2 (6.5) 0 (0) 2 (7.1) 0.99 - History of obstetric-gynecologic surgery (%) 3 (9.7) 0 (0) 3 (10.7) 0.99 - Oral contraceptive using (%) 3 (9.7) 0 3 (10.7) 0.66 SSc clinical characteristics - Disease duration (years); mean ± SD 9.7 ± 7.5 9.3 ± 4.8 9.8 ± 7.8 0.92 - dcSSc subset (%) 21 (67.7) 3 (100) 18 (64.3) 0.53 - mRSS; mean ± SD 9.9 ± 7.7 12 ± 3.5 9.7 ± 8.1 0.64 -Raynaud’s phenomenon (%) 29 (93.6) 3 (100) 26 (92.9) 0.99 - Salt and pepper appearance (%) 21 (67.7) 3 (100) 18 (64.3) 0.53 - Telangiectasia (%) 7 (22.6) 2 (66.7) 5 (17.9) 0.12 - Edematous skin (%) 12 (38.7) 2 (66.7) 10 (85.7) 0.54 - Arthritis (%) 6 (19.4) 0 (0) 6 (21.4) 0.99 - Muscle weakness (%) 3 (9.7) 0 (0) 3 (10.7) 0.99 - Esophageal involvement (%) 7 (22.6) 0 (0) 7 (25.0) 0.99 - Stomach involvement (%) 4 (12.9) 1 (33.3) 3 (10.7) 0.35 - Pulmonary hypertension (%) 1 (3.2) 0 (0) 1 (3.6) 0.99 - Interstitial lung disease (%) 15 (55.6) 2 (66.7) 13 (54.2) 0.99 Serology - Anti-topoisomerase-I antibody positive (%) 20 (71.4) 3 (100) 17 (68.0) 0.54 - Anti-centromere antibody positive (%) 1 (8.3) 0 (0) 1 (10.0) 0.99 - ESR > 25 mm/h (%) 13 (43.3) 1 (33.3) 12 (44.4) 0.99 Medication Cyclophosphamide - Using (%) 15 (48.4) 3 (100) 12 (42.9) 0.10 - Cumulative dose (g); median (IQR) 0 (0–16.8) 37.1 (13–38.3) 0 (0–13.4) 0.02* - Duration of used (days); median (IQR) 0 (0–570) 660 (365–960) 0 (0–300) 0.02* - Starting age (years); median (IQR) 37 (32–38) 27 (19–33) 37 (35–38.5) 0.02* Prednisolone - Cumulative dose (g); median (IQR) 2.8 (0.6–9.1) 2.6 (2.5–2.7) 2.9 (2.5–9.9) 0.62 - Duration of used (days); median (IQR) 540 (90–1260) 525 (510–540) 570 (90–1350) 0.90 - Starting age (years); median (IQR) 35 (27–37.5) 23 (19–27) 35 (31–38) 0.10

BMI body mass index, dcSSc diffuse cutaneous systemic sclerosis, ESR erythrocyte sedimentation rate, IQR interquartile range, mRSS modified Rodnan skin score, SSc systemic sclerosis *Statistical significant with low ovarian reserve was recorded: 18 of the patients gave scleroderma [18], one with lcSSc [17], and an observation birth—in 3 of whom it was after their SSc diagnosis. study from the USA [16]. The previous reports had limited information about the clinical characteristics of the patients with POI. In order to characterize POI in SSc, we performed Discussion an analytical cross-sectional study that surveyed clinical char- acteristics used to define the clinical associations of POI in POI is uncommon in SSc. To date, there have been a few case SSc. We found a low prevalence of POI in Thai SSc patients; reports of POI in SSc patients, one in patients with localized however, the prevalence was higher than that of a previous Clin Rheumatol

Table 2 Clinical characteristics of the patients with POI much higher than in patients without POI (37.1 g vs. 0 g and Clinical characteristics Case 1 Case 2 Case 3 660 days vs. 0 days, respectively), while the starting age for CYC treatment in patients with POI was younger than that of Demographic patients without POI. The univariate analysis revealed that the -Age(years) 303638 independent factors associated with POI among Thai SSc - BMI (kg/m2) 17.1 15 18.8 were a high cumulative dose, long duration of CYC used, - Oral contraceptive using No No No and young age when starting CYC treatment. The results are SSc clinical characteristics comparable with the association between CYC used and ovar- - Disease duration (years) 12 3 11 ian failure in systemic lupus erythematosus (SLE) patients. - SSc subset dcSSc dcSSc dcSSc Many studies found that permanent ovarian failure in SLE - Esophageal involvement No Yes No patients depended on the age starting CYC, notably above - Stomach involvement Yes No Yes 32 years of age, and cumulative dose of CYC regardless of - Pulmonary hypertension No No No route of administration [37–39]. However, there was a pro- - Interstitial lung disease Yes Yes No spective study that revealed the low incidence of side effects Serology including premature ovarian failure after low-dose intrave- - Anti-topoisomerase-I antibody Positive Positive Positive nous CYC therapy in SSc patients [40]. - Anti-centromere antibody Negative Negative Negative The low numbers of POI in our study resulted in a statisti- Medication cal limitation so that no multivariate analysis could be done to Cyclophosphamide determine the final model of factors associated with POI. - Cumulative dose (g) 38.3 13 37.1 Nevertheless, our results have value for making the attending - Duration of used (days) 660 365 960 physician aware of the risks and benefits of CYC treatment of - Starting age (years) 19 33 27 reproductive age and female SSc patients. In cases where Prednisolone CYC therapy is required in SSc women of childbearing age, - Cumulative dose (g) 2.7 8.1 2.5 fertility preservation (i.e., ovarian tissue preservation or oo- cyte or embryo cryopreservation) and potential risks of using - Duration of used (days) 540 810 510 assistive reproductive technology should be discussed with - Starting age (years) 19 33 27 the patient and her spouse before starting treatment. BMI body mass index, dcSSc diffuse cutaneous systemic sclerosis, SSc In contrast to the prevalence of POI, early menopause was systemic sclerosis revealed in around one-third of Thai SSc patients. In addition, the prevalence of early menopause among SSc patients was higher than in the normal population [14] (i.e., 32.3% vs. 5%, study from the USA (10%vs.3%) [16] and higher than the respectively). As our initial analysis, the factors associated overall prevalence of POI (viz., 1%) [12, 13]. The higher with early menopause among SSc patients were old age, long prevalence of POI among Thais vs. Americans might be due disease duration, and the medication (i.e., particularly high to the higher proportion of dcSSc among Thais than cumulative doses of CYC, prolonged use of CYC, and high Americans [16, 32]. Our study revealed that all of the patients cumulative dose of prednisolone used). The high prevalence with POI had the dcSSc subset. According to the nature of of early menopause in SSc over against the normal population dcSSc, it is a severe form of SSc, which leads to widespread might be explained by the exposure to medications that can organ fibrosis. There is, however, no current data supporting affect the sex hormone (steroid) and ovarian function (CYC). whether fibrosis is revealed in the ovaries or affecting ovarian Even though the cumulated dose of CYC in patients with early — function. Further study of ovarian fibrosis particularly menopause seemed to be less than that in patients with POI, — among patients with the dcSSc subset is suggested. the age on starting CYC treatment in the former was older than CYC is the most important factor associated with POI in in the latter. Moreover, the patients with early menopause SSc patients. CYC is an alkylating agent that is commonly were older when starting CYC than patients without meno- prescribed for interstitial lung treatment in SSc [33]. The pause, albeit the difference was not statistically significant. mechanism of CYC decreased DNA synthesis and induced The findings might be due to age-related ovarian reserve apoptosis [34]. The metabolism of CYC results in cytotoxic (viz., older age, less ovarian reserve). Our results resemble a metabolites, especially phosphamide mustard, which causes study on SLE, which found that the rate of sustained amenor- ovarian damage by inducing oocytes and somatic granulosa rhea in SLE depended upon the age when CYC was started cells apoptosis [35]. The previous data showed that POI (i.e., 12% ≤ 25, 27% between 26 and 30, and 62% ≥ 31 years depended on the starting age, dose, and duration of CYC of age) [39]. In addition to POI, we did not do a multivariate treatment [36]. In our study, the median cumulative dose of analysis to determine the final model of factors associated oral CYC and duration of CYC used in patients with POI was with early menopause because of the low number of events, Clin Rheumatol

Table 3 Clinical association with early menopause

Characteristic Early menopause No early menopause p value N =10 N =18

Demographic - Age (years); mean ± SD 43.6 ± 1.5 37 ± 6.6 0.004* - BMI (kg/m2); median (IQR) 20 (17.9–26.2) 20.4 (18.4–22.6) 0.58 - Dyslipidemia (%) 1 (10) 3 (14.3) 0.99 - Hypothyroidism (%) 0 (0) 1 (4.8) 0.99 - Hyperthyroidism (%) 2 (20) 0 (0) 0.09 - History of obstetric-gynecologic surgery (%) 0 (0) 3 (14.3) 0.53 - Oral contraceptive using (%) 1 (10) 2 (11.1) 0.80 SSc clinical characteristic - Disease duration (years); mean ± SD 14.3 ± 10 7.5 ± 5 0.02* - dcSSc subset (%) 7 (70) 14 (66.7) 0.99 - mRSS; mean ± SD 12.2 ± 10.5 8.9 ± 6 0.27 -Raynaud’s phenomenon (%) 9 (90) 20 (95.2) 0.99 - Salt and pepper appearance (%) 7 (70) 14 (66.7) 0.99 - Telangiectasia (%) 2 (20) 5 (23.8) 0.99 - Edematous skin (%) 2 (20) 10 (47.6) 0.24 - Arthritis (%) 3 (30) 3 (14.3) 0.36 - Muscle weakness (%) 2 (20) 1 (4.8) 0.24 - Esophageal involvement (%) 3 (30) 4 (19.1) 0.65 - Stomach involvement (%) 0 (0) 4 (19.1) 0.28 - Pulmonary hypertension (%) 1 (10) 0 (0) 0.32 - Interstitial lung disease (%) 5 (55.6) 10 (55.6) 0.99 Serology - Anti-topoisomerase-I antibody positive (%) 5 (55.6) 15 (79) 0.37 - Anti-centromere antibody positive (%) 1 (20) 0 (0) 0.42 - ESR > 25 mm/h (%) 2 (20) 11 (55) 0.12 Medication Cyclophosphamide - Using (%) 8 (80) 4 (22.2) 0.01* - Cumulative dose (g); median (IQR) 13.4 (2.4–18) 0 (0–3.8) 0.03* - Duration of used (days); median (IQR) 405 (90–660) 0 (0–180) 0.03* - Starting age (years); median (IQR) 37 (36–37.5) 33 (27–39) 0.18 Prednisolone - Cumulative dose (g); median (IQR) 8.6 (2.7–15.9) 2.6 (0–5.5) 0.02* - Duration of used (days); median (IQR) 1155 (450–2280) 480 (0–810) 0.05 - Starting age (years); median (IQR) 36 (35–37) 31.5 (22–38) 0.13

BMI body mass index, dcSSc diffuse cutaneous systemic sclerosis, ESR erythrocyte sedimentation rate, IQR interquartile range, mRSS modified Rodnan skin score, SSc systemic sclerosis *Statistical significant making it impossible to conclude on factors associated with The cumulated dose of prednisolone used was an indepen- early menopause in SSc patients. Our results nevertheless dent factor for early menopausal development in SSc by uni- could help make attending physicians aware of the long- variate analysis. High-dose glucocorticoid is associated with a term effects CYC on female gonadal function. Thus, prescrip- reduction of FSH and LH by suppression of the hypothalamic- tions for CYC for female sufferers of SSc—both for young pituitary-adrenal axis; this leads to a reduction of the adreno- patients of reproductive age and premenopausal middle-aged cortical hormone due to negative feedback regulation. women—should be concerned of the long-term effects. Subsequently, decreases in the gonadotropin-releasing Clin Rheumatol hormone result in a decrease in FSH and LH secretion causing ovarian response to exogenous gonadotropin usually have irregular menstruation and amenorrhea [41, 42]. Although all disappointing assisted reproductive outcomes. In our study, of our SSc patients received only low-dose corticosteroid— the median AMH value in SSc patients was 0.035 ng/mL, equivalent to prednisolone < 15 mg/day—to reduce the risk of and most of the SSc patients had low ovarian reserve renal crisis, the high cumulated dose of prednisolone treat- (90.3%). Such findings reflect the fact that those patients have ment (low-dose but long duration) might affect and/or sup- an increased risk of unsuccessful outcomes in ART and need press FSH and LH production by the aforementioned mecha- specific protocols to achieve better outcomes according to the nism. There are, however, no recent data supporting the hy- newly proposed criteria for classifying outcomes pothesis. According to the principle of steroid used among [28]. AMH should, however, be carefully interpreted in some SSc, CYC is likely to be prescribed in combination with pred- conditions that can affect the AMH level (i.e., Crohn’sdis- nisolone. It is possible that the association between cumulated ease, SLE, and chemotherapy including CYC) [10]. Owing to dose of prednisolone and early menopause might be explained the limited data on prevalence, the clinical association of in- by the concomitant used of prednisolone and CYC. fertility, and ART outcomes in young females with SSc, fur- Multivariate analysis can adjust the confounders and deter- ther study of fertility in SSc with the age-matched control mine those that best associated with early menopause among group particularly in reproductive age women needs to be SSc patients. Unfortunately, multivariate analysis is unable for investigated. evaluation the final model of factors associated with early Our study had some limitations: (a) a small population menopause in our study due to the low numbers of patients related to the epidemiology of the disease which has a low with early menopause. However, our results provided prelim- proportion of younger aged females with SSc; (b) not all pa- inary information that prolonged use of steroid, even in low- tients signed the consent for a gynecological examination and dose with and without CYC, in SSc patient needs to be mon- transvaginal ultrasound, so results from those patients were itored for early menopausal development. excluded; and (c) no information about ovarian volume and Various gynecologic problems were detected in SSc pa- ovarian stromal blood flow; however, the available tests pro- tients, of which ovarian cyst was the most common (31%), vided sufficient information to answer research questions and followed by menopausal symptoms (27%) and vaginal atro- determine the ovarian reserve in SSc patients according to the phy (19%). Bhadauria et al. [16] found that gynecologic prob- guideline from Practice Committee of the American Society lems in SSc included vaginal dryness (71%), dyspareunia for Reproductive Medicine [45]. The strengths of our study (56%), and vaginal ulcer (23%). In contrast to our study, vag- are as follows: (a) this is the first study to determine the clin- inal problems were not as common as previously reported. ical association with POI and early menopause and evaluate The vaginal problems among Thai SSc included vaginal atro- the ovarian reserve in SSc; (b) common clinical parameters phies (19%) and dyspareunia (15%). We did not further in- associated with POI and/or early menopause in SSc patients vestigate whether patients had Sjögren syndrome, which is a were included; and (c) we conducted a gynecological problem common related disease with vaginal dryness in SSc. The assessment using gynecological examination and transvaginal vaginal dryness and dyspareunia may affect sexual dysfunc- ultrasound. We thus provide information about genital and tion, such as decreased number and intensity of orgasm and ovarian problems in SSc. Our findings should be helpful for impact on the quality of life [43]. Screening for vaginal dry- attending physicians so that they might use a multidisciplinary ness and dyspareunia is suggested among female SSc patients approach with gynecologists in order to improve care for fe- in order to schedule a gynecological consultation and treat- male SSc patients. ment for improved quality of life. Ovarian insufficiency may be a lesser concern for the SSc patient who has decided not to have any more children. Still, Conclusion for a young female patient who wishes to have children, the issue remains relevant. Apart from POI, SSc patients have POI in Thai SSc was uncommon, whereas early menopause multiple risk factors for infertility, including physical factors and low ovarian reserve were frequently revealed. A high (i.e., skin tightness or joint contracture, dyspnea from lung cumulative dose of CYC was associated with both POI and pathology, and psychological factors about self-esteem and early menopause among SSc patients. The reproductive out- body image) [5]. Even when ART is applied for infertility comes therefore should be aware. management, the success rate is between 20 and 30% [44]. Multiple parameters are used to measure the clinical success Acknowledgments The authors thank (a) the Scleroderma Research of ART. Ovarian reserve markers—including AMH and Group and the Faculty of Medicine, Khon Kaen University for support AFC—are currently accurate parameters for ovarian reserve (Grant Number IN62236), (b) the Thai Rheumatism Association for the support, and (c) Mr. Bryan Roderick Hamman under the aegis of the measurement, and these can predict ovarian response after Publication Clinic Khon Kaen University, Thailand, for assistance with IVF [8]. Patients who have impaired ovarian reserve or a poor the English language presentation. Clin Rheumatol

Authors’ contributions AJ did the data collection and drafted the manu- clinical management. J Endocrinol Investig 38:597–603. https:// script. CF designed the study and did data analysis. LS did the data doi.org/10.1007/s40618-014-0231-1 collection and study design. NE did the data collection. LS, NE, AM, 10. Tal R, Seifer DB (2017) Ovarian reserve testing: a user’sguide.Am SS, and CF proofread the manuscript. CF approved the manuscript. J Obstet Gynecol 217:129–140. https://doi.org/10.1016/j.ajog. 2017.02.027 Funding The study received funding support from Faculty of Medicine, 11. van der Stege JG, Groen H, van Zadelhoff SJN et al (2008) Khon Kaen University, Thailand (Grant Number IN62236). Decreased concentrations and diminished general and sexual well-being in women with premature ovarian failure. Menopause 15:23–31. https://doi.org/10.1097/gme. Data availability Data or materials are available upon request. 0b013e3180f6108c 12. 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