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Prevalence and Clinical Associations with Premature Ovarian Insufficiency, Early Menopause, and Low Ovarian Reserve in Systemic Sclerosis

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Prevalence and Clinical Associations with Premature Ovarian Insufficiency, Early Menopause, and Low Ovarian Reserve in Systemic Sclerosis Clinical Rheumatology https://doi.org/10.1007/s10067-020-05522-5 ORIGINAL ARTICLE Prevalence and clinical associations with premature ovarian insufficiency, early menopause, 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 pregnancy 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 oocytes and fol- licles during life [9]. AFC is a marker representing the total Operational definition number of antral follicles in both ovaries, 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]. Oocyte 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
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