Account

Reproductive Endocrinology · Ovulation Physiology

Non-steroidal anti-inflammatory drug induces luteinized unruptured follicle syndrome in young female juvenile idiopathic arthritis patients

Tomioka RB, Ferreira GRV, Aikawa NE, Maciel GAR, Serafini PC, Sallum AM, Campos LMA, Goldestein-Schainberg C, Bonfá E, Silva CA

Published July 14, 2018 Clinical Rheumatology, 37(10), 2869-2873
DOI 10.1007/s10067-018-4208-x PMID 30003441

Abstract

To assess prospectively luteinized unruptured follicle (LUF) syndrome in juvenile idiopathic arthritis (JIA) patients with and without non-steroidal anti-inflammatory drugs (NSAIDs) and healthy controls. Twenty-three adolescent and young adult female JIA patients (ILAR criteria) and 11 female healthy subjects were studied by pelvic ultrasound monitoring for follicular development and ovulation in one menstrual cycle. LUF syndrome was prospectively investigated by pelvic ultrasound with a dominant ovarian follicle without signs of follicular rupture, with elevation of serum progesterone in the luteal phase of the menstrual cycle and luteinizing hormone (LH) detected in the urine. Comparison between JIA patients with (n = 8) vs. without NSAIDs (n = 15) and healthy controls (n = 11) revealed that LUF syndrome was significantly higher in the former group (2 (25%) vs. 0% vs. 0%, p = 0.049). These two patients with LUF syndrome had normal menstrual cycles without reduced ovarian reserve, and they were under naproxen 500 mg bid during the menstrual cycle. Disease duration was comparable in JIA with and without NSAIDs [19.8 (4.4-25) vs. 13 (3.1-33) years, p = 0.232]. Further comparison between JIA patients with and without NSAIDs and healthy controls showed similar mean anti-Müllerian hormone levels (p = 0.909), estradiol (p = 0.436), FSH (p = 0.662), LH (p = 0.686), and mean antral follicle count (p = 0.240) and ovarian volume (p = 0.363). No differences were evidenced in three groups regarding Caucasian race, body mass index, duration, and length of menstrual cycles (p > 0.05). This is the first study to identify that JIA patients have a high frequency of LUF without impaired ovarian reserve. Future prospective studies are necessary to determine if chronic/continuous use of NSAIDs in JIA will have an impact in these patients' fertility.

Topics

By this author

Metabolic and Endocrine Agents · Corticosteroids

The effects of spironolactone on adrenal steroidogenesis in hirsute women

Serafini P et al., 1985 Fertil Steril

The effect of spironolactone on adrenal androgen and cortisol production was studied in six hirsute women. Hirsute women were evaluated before and 1 month after receiving 200 mg of spironolactone daily. Basal levels of serum androgens, 17-hydroxyprogesterone (17-OHP), cortisol (F), corticosteroid-binding globulin, and plasma adrenocorticotropic hormone (ACTH) were normal and did not change with therapy. The delta maximum (delta max) responses after dexamethasone suppression and ACTH administration of dehydroepiandrosterone (DHEA), androstenedione (delta 4A), 17-hydroxypregnenolone, and 17-OHP were similar in hirsute women and ovulatory control subjects. After spironolactone administration, the delta max DHEA response was unchanged, whereas the delta max delta 4A response was decreased (P less than 0.05). The delta max ratios of DHEA/delta 4A and 17-OHP/delta 4A were significantly increased after spironolactone in hirsute women, which suggested inhibitions of 3 beta-ol-dehydrogenase-isomerase and delta 4 17,20 desmolase activities. A significant reduction in delta max F occurred after spironolactone administration (P less than 0.05). Although baseline 11-desoxycortisol (S) and the plasma S/ACTH ratio were unaltered, the delta max S/F ratio increased after treatment (P less than 0.01), suggesting an inhibition of 11 beta-hydroxylase activity. Inhibition of adrenal androgen production occurs with spironolactone, but only serum levels of delta 4A are decreased, whereas DHEA and its sulfate (DHEA-S) levels remain unchanged.

Related research

Ovulation Physiology · Luteinized Unruptured Follicle Syndrome

Luteinized unruptured follicle syndrome increased by inactive disease and selective cyclooxygenase 2 inhibitors in women with inflammatory arthropathies

Micu MC et al., 2011 Arthritis Care Res (Hoboken)

Administration of nonsteroidal antiinflammatory drugs (NSAIDs) may impair fertility. The occurrence of the luteinized unruptured follicle (LUF) syndrome was assessed in women with inflammatory arthropathies exposed to NSAIDs and compared to that in nonexposed women. Fourteen patients with inflammatory rheumatic disease, 29 women with noninflammatory musculoskeletal conditions, and 449 women not exposed to NSAIDs were studied by intravaginal ultrasound monitoring for follicular development and ovulation in 1 or more menstrual cycles. Disease activity was assessed in inflammatory rheumatic disease. In 59 monitored cycles of patients with continuous NSAID exposure, 35.6% of LUF syndromes occurred compared to 3.4% of LUF syndromes in untreated women (P < 0.001). Etoricoxib was responsible for 75% of LUF syndromes in patients exposed continuously, whereas diclofenac generated 15% of LUF syndromes. An ibuprofen dosage of 1,600 mg/day did not induce LUF syndrome either at continuous periovulatory or discontinuous exposure. Interestingly, the frequency of LUF syndrome was 46.2% in patients with inactive inflammatory disease compared to 15% in patients with active disease (P = 0.023). Etoricoxib generated LUF syndrome in 94.2% of the cases with inactive disease versus 28.6% in patients with active disease (P = 0.003). NSAIDs increased the risk of the LUF syndrome, particularly in patients with inactive disease. The selective cyclooxygenase 2 (COX-2) inhibitor etoricoxib was a more potent inductor of LUF syndrome than nonselective COX inhibitors. Continuous periovulatory exposure to NSAIDs should be avoided when planning a pregnancy in patients with rheumatic diseases.

Ovulation Physiology · Anovulation

Non-steroidal anti-inflammatory drugs as a possible cause for reversible infertility

Mendonça LL et al., 2000 Rheumatology (Oxford)

To highlight the possible association between infertility and treatment with long-term non-steroidal anti-inflammatory drug (NSAIDs). NSAIDs act mainly through the inhibition of cyclooxygenase, the enzyme that catalyses the synthesis of prostaglandins, which are essential mediators of ovulation, implantation and placentation of the conceptus. Case reports of four women suffering from severe arthritis, on long-term NSAIDs and undergoing extensive investigation and treatment for infertility. During the last 2 yr, four out of five women with severe arthritis and difficulty conceiving were counselled to stop NSAIDs, and they successfully conceived shortly after the withdrawal of NSAIDs. NSAIDs, used largely for the treatment of rheumatological conditions, may be responsible for some cases of infertility.

Ovulation Physiology · Luteinized Unruptured Follicle Syndrome

Incidence of the luteinized unruptured follicle phenomenon in cycling women

Kerin JF et al., 1983 Fertil Steril

A prospective study is presented in order to determine the frequency of the luteinized unruptured follicle (LUF) in a population of 66 regularly cycling women. They were monitored by daily ultrasound for a total of 183 cycles, and the LUF was detected in 9 cycles, giving an incidence of 4.9%. The results of daily changes of luteinizing hormone, estradiol, and progesterone provide support for the thesis that the LUF behaves steroidogenically as a corpus luteum and that the luteal phase duration is normal. Continued monitoring in 35 cycles revealed a recurrence in only one case during a fourth subsequent cycle. Thus, the findings indicate that the LUF is a sporadic and infrequent phenomenon. It is therefore an uncommon cause of infertile cycles in potentially fertile women and represents a biologic variable rather than a syndrome. Based on ultrasonic and endocrine observations, a mechanism is proposed for the resolution of the LUF.

Ovulation Physiology · Luteinized Unruptured Follicle Syndrome

Comparison of various therapies for the luteinized unruptured follicle syndrome

Check JH et al., 1992 Int J Fertil

A study was initiated to evaluate the prevalence of the luteinized unruptured follicle (LUF) syndrome in a group of 355 women with infertility. The diagnosis was established by carefully observing daily sonograms along with measuring estradiol, progesterone, and luteinizing hormone (LH) levels. Two distinct types of LUF syndrome were identified: mature follicle LUF, in which release of an ovum was not demonstrated after a follicle attained maturity (serum estradiol reached 200 pg/mL while serum progesterone remained less than 2.5 ng/mL), versus premature luteinization LUF, where the serum progesterone increased above 2.5 ng/mL before follicular maturation was attained. The use of either hCG alone or hCG in combination with hMG in a single injection at the time of follicular maturation successfully corrected mature follicle LUF in 21 of 46 patients (46%), whereas ovulation-inducing drugs plus hCG or hCG and hMG corrected LUF in 24 of 25 patients (96%). Clomiphene citrate proved inferior to hMG in that it corrected LUF in 3 of 25 patients (12%) versus 12 of 22 patients (95%) who had undergone hMG therapy. Thus, hMG-hCG therapy is the most efficacious for mature follicle LUF, but because release can occur spontaneously on occasion by an appropriately timed single gonadotropin injection, one could offer the less costly options first. For premature luteinization, speeding up follicular maturation with gonadotropin therapy is effective. Upon failure of this technique, the more costly endogenous gonadotropin suppression followed by hMG can be employed.

Reproductive Endocrinology › Ovulation Physiology › Luteinized Unruptured Follicle Syndrome · Menstrual Cycle › Cycle Disorders › Ovulatory Disturbances · Diagnostics › Ultrasound › Follicular Monitoring
Nadia E Aikawa, Gustavo A R Maciel, Lucia M A Campos, Eloisa Bonfá, Clovis A Silva, Gabriela R V Ferreira, Claudia Goldestein-Schainberg, Renato B Tomioka
N Aikawa, G Maciel, L Campos, E Bonfá, C Silva, G Ferreira, C Goldestein-Schainberg, R Tomioka
PMID 30003441 30003441 DOI 10.1007/s10067-018-4208-x 10.1007/s10067-018-4208-x Tomioka et al. 2018, Tomioka 2018

Cite this article

Tomioka, R., Ferreira, G. R. V., Aikawa, N. E., Maciel, G. A. R., Serafini, P., Sallum, A., campos, L., Goldestein-Schainberg, C., Bonfa, E., & Silva, C. (2018). Non-steroidal anti-inflammatory drug induces luteinized unruptured follicle syndrome in young female juvenile idiopathic arthritis patients. Clinical rheumatology, 37(10), 2869-2873. https://doi.org/10.1007/s10067-018-4208-x

Keywords

Anti-Inflammatory Agents, Non-Steroidal

Learn

Resources

Tools

Help

Candid Platinum Transparency 2026

RRM Academy is a 501(c)(3) nonprofit providing free and low-cost education in restorative reproductive medicine for patients and healthcare professionals.

This site is an educational resource and does not provide medical advice. Inclusion of a study does not imply endorsement of its findings. Always consult a qualified healthcare provider for diagnosis and treatment.

© 2026 RRM Academy · All Rights Reserved

Restorative Reproductive Medicine Foundation · 3401 Hartzdale Dr, Ste 103B PMB 3518, Camp Hill, PA 17011 · EIN: 93-4594315
Sitemap AI Instructions Developers Terms of Use Medical Disclaimer Privacy Policy