Precocious Puberty and Subsequent Primary Ovarian Insufficiency in an Adolescent With Latent Tuberculosis

To the Editors: Primary ovarian insufficiency (POI) affects approximately 1% of women under age 40, with even fewer cases occurring in adolescence. POI is characterized by amenorrhea, hypergonadotropic hypogonadism and low estrogen levels. Common etiologies include genetic disorders (eg, Turner syndrome, Fragile X premutation), autoimmune diseases, iatrogenic causes and, less commonly, infectious etiologies such as tuberculosis (TB). In regions where TB is endemic, genital TB is a well-known cause of infertility, yet its relationship with POI, particularly in high-income countries, is underrecognized. We present an unusual case of a patient with early precocious puberty followed by POI in the setting of prior latent TB infection. A 17-year-old G0P0 female with a history of hypermobility syndrome and latent TB presented for evaluation of secondary amenorrhea and abnormal menstrual cycles. She was adopted from Russia at age 3.5 with no known family history. At that time, she had a strongly positive purified protein derivative at 20 mm, which was placed and read by her primary care provider. A chest radiograph was negative, and a QuantiFERON test obtained later was also negative. After discussion between her primary physician and pediatric ID consultants, a consensus was reached that the patient should be treated for latent TB. She subsequently completed a 9-month course of isoniazid by June 2012 with no evidence of reactivation on follow-up. At age 8.5, she exhibited signs of precocious puberty and was found to have a bone age of 12 years. She was started on Depot Lupron with a goal of suppression of the hypothalamic-pituitary-gonadal axis and remained on therapy until age 11.5. After cessation, she progressed through puberty, with menarche occurring at age 12 suggesting reversible axis suppression. However, her menses were irregular and ceased entirely by age 14. Initial work-up at that time revealed elevated gonadotropins (follicle-stimulating hormone 151 mIU/mL; ref <10, leutinizing hormone 85.5 mIU/mL; ref <10), estradiol <15 pg/mL, anti-Mullerian hormone 0.1 ng/mL, inhibin B <10 pg/mL and 17-hydroxyprogesterone 14 ng/dL. Adrenal antibodies were negative. Karyotype was 46,XX, and expanded genetic testing was negative for Fragile X premutation, cystic fibrosis transmembrane conductance regulator, spinal muscular atrophy and hemoglobinopathies. Thyroid function was normal except for mildly elevated thyroid peroxidase antibodies. Pelvic ultrasound showed a normal uterus with small ovarian volumes (0.43 and 0.5 mL; normative mean ~2–4 mL for this age group). Magnetic resonance imaging of the brain (T1/T2 sequences, nonenhancing) showed a 1 × 3 mm pars intermedia lesion, favored Rathke cleft cyst or microadenoma, without mass effect. Bone age at 16 years 11 months was 15 years, consistent with delayed maturation before hormone therapy initiation. She was started on estradiol and cyclic progesterone therapy, which resumed regular withdrawal bleeding. She denied vasomotor symptoms or other signs of hypoestrogenism. Family history was unavailable due to adoption, though her maternal half-sister (also adopted) reportedly had normal menses and no signs of pubertal abnormality. This case illustrates an unusual sequence of idiopathic precocious puberty followed by early POI. The most common causes of POI in adolescents include chromosomal abnormalities, Fragile X premutation and autoimmune disorders, all of which were ruled out in this case. Infectious causes, including mumps and TB, are less frequently considered.1 TB, particularly genital TB, is a known cause of infertility and tubal factor damage.2 Ovarian involvement is less common but documented. While genital TB is typically a postpubertal disease, latent TB in early childhood may result in subclinical damage to the hypothalamic-pituitary-ovarian axis or direct ovarian impairment. Her early exposure to TB and lack of other explanations raise the possibility of a postinfectious etiology for her ovarian failure.3 Although genital TB was never diagnosed, the early latency and lack of alternative explanation warrant consideration. It is also possible that TB infection may have contributed to dysregulation of pubertal timing, leading first to premature activation and later to depletion of follicular reserve. A growing body of literature suggests TB, including latent and extrapulmonary forms, can contribute to reproductive dysfunction. Chu et al1 found associations between latent TB and impacted ovarian reserve. Additionally, a case reported by Roy et al2 described a rare presentation of primary ovarian TB. Tripathy et al3 found that congenital TB had a detrimental impact on fertility. The intersection of precocious puberty and POI is rare and may suggest accelerated depletion of ovarian follicles, especially in the absence of structural or genetic anomalies. The presence of hypermobility syndrome in this case does not currently have a known link to POI. This case highlights the importance of considering infectious etiologies, including remote latent TB, in adolescents with unexplained POI, particularly when classic causes have been ruled out. Early life TB exposure may contribute to atypical reproductive trajectories, and greater awareness is warranted among pediatric and adolescent gynecologists. ACKNOWLEDGMENTS We thank the patient and her guardian for granting permission to share this case.