Amenorrhea during thalidomide treatment: An unusual cause of ovarian failure?

Pulido-Pérez, Ana; Lázaro-Ochaita, Pablo; Suárez-Fernández, Ricardo

doi:10.1016/j.medcle.2017.06.036

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"tieneTextoCompleto" => true "saludo" => "Dear Editor," "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "135" "paginaFinal" => "136" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Ana Pulido-Pérez, Pablo Lázaro-Ochaita, Ricardo Suárez-Fernández" "autores" => array:3 [ 0 => array:4 [ "nombre" => "Ana" "apellidos" => "Pulido-Pérez" "email" => array:1 [ 0 => "ana.pulido@salud.madrid.org" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "Pablo" "apellidos" => "Lázaro-Ochaita" ] 2 => array:2 [ "nombre" => "Ricardo" "apellidos" => "Suárez-Fernández" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Servicio de Dermatología, Hospital General Universitario Gregorio Marañón, Madrid, Spain" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Amenorrea durante el tratamiento con talidomida: ¿una causa infrecuente de disfunción ovárica?" ] ] "textoCompleto" => "Although thalidomide is currently approved for use in the treatment of patients with multiple myeloma aged 65 years or older, for years, its indication has been extended to other conditions of inflammatory origin. Although initially marketed as a sedative drug with antiemetic properties, its mechanism of action involves a potent immunomodulatory and anti-inflammatory effect. However, after being involved in an epidemic of congenital malformations in women who had received the drug during the first trimester of pregnancy, it was withdrawn from the market and started to be used in a timely and controlled manner in autoimmune diseases and type 2 leprosy reactions.<a class="elsevierStyleCrossRef" href="#bib0030">1</a> Severe teratogenicity, peripheral neuropathy, hematologic disorders (neutropenia, lymphopenia, anaemia, thrombocytopenia) and increased risk of thromboembolic events are among its main side effects. Menstruation disorders, including amenorrhea, have been described in women of childbearing age treated with thalidomide<a class="elsevierStyleCrossRef" href="#bib0035">2</a>; however, as described in its Summary of Product Characteristics, it should be assumed that amenorrhea during treatment with thalidomide is due to pregnancy, unless confirmed otherwise.We report the case of a 30-year-old Brazilian woman diagnosed with erythema nodosum leprosum as a form of onset of subpolar lepromatous leprosy. Initially, she received specific treatment for the disease (rifampicin, clofazimine and dapsone) along with prednisone at doses of 1mg/kg/day. Two months after the diagnosis, oral steroids were discontinued and thalidomide was started, when the patient developed a state of dependence on corticosteroids that did not allow down-titration with prednisone. The patient agreed to maintain absolute and continuous sexual abstinence. Pregnancy tests were performed monthly under strict medical supervision. After achieving control of the reaction episodes, in the absence of steroid treatment, and after completing the specific treatment for the disease (12 months), she received thalidomide monotherapy at a dose of 100mg per day. A delay in the menstruation was detected in the following 6 months, which forced the suspension of the treatment. Pregnancy was ruled out by serum quantification of the β subunit of human chorionic gonadotropin, the tests were repeated together with a transvaginal ultrasound at 6 weeks. No family history of early menopause was found in the focused case history inquiry, nor the administration of drugs or herbal preparations other than those described during her follow-up. A complete gynaecological study, blood and urine lab tests, as well as an exhaustive case history were conducted, ruling out other causes of secondary amenorrhea: tumours, ovarian polycystic disease, thyroid disorders, psychiatric disorders, sudden changes in body mass index, among others. FSH and LH levels were elevated (FSH 24UI/1, LH 19UI/l; menopausal range: FSH 20–100UI/LH 15–70UI/1), progesterone 0.1mg/l (menopausal range: 0.1–1.6mg/l), estradiol was slightly decreased (24ng/l; menopausal range: 10–25ng/l) and prolactin, within the parameters of normality (16mg/l). Secondary amenorrhoea of possible pharmacological origin (assessed using Naranjo's algorithm for the evaluation of an adverse drug reaction) was diagnosed and a levonorgestrel-releasing intrauterine device was implanted.Amenorrhea during treatment with thalidomide is considered a rare side effect (prevalence of 0.02%).<a class="elsevierStyleCrossRef" href="#bib0040">3</a> Most cases have been described in women treated with thalidomide for inflammatory or autoimmune diseases, which may be explained by the increased prevalence of multiple myeloma in postmenopausal women. The latency period from the introduction of the drug to amenorrhea is approximately 6 months, although there are cases in which it can take more than 3 years, regardless of the dose received or accumulated. The pathogenic mechanism by which it is produced is unknown, although the presence of elevated levels of FSH/LH and the decrease in oestrogens (hypergonadotropic hypogonadism), in the absence of pituitary disease, show that thalidomide could induce ovarian dysfunction. Generally, amenorrhea is reversible upon discontinuation of the drug (mean of 3 months).<a class="elsevierStyleCrossRef" href="#bib0045">4</a>Although the relationship between the reaction episodes and the development of amenorrhea could be considered in the case reported, the fact is that ovarian involvement in women with multibacillary leprosy has been poorly studied. In the cases described, a higher incidence of irregular menses and fertility disorders has been found, rather than true amenorrhea, without adequately documented administration of thalidomide in leprosy reaction patients.<a class="elsevierStyleCrossRef" href="#bib0050">5</a>For obvious reasons, amenorrhea represents the symptom most feared by clinicians treating young women with thalidomide, and although pregnancy is the main cause to rule out, recognizing its role as a pharmacological agent responsible for reversible ovarian dysfunction is essential in the follow-up of these patients." "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Pulido-Pérez A, Lázaro-Ochaita P, Suárez-Fernández R. Amenorrea durante el tratamiento con talidomida: ¿una causa infrecuente de disfunción ovárica? Med Clin (Barc). 2017;149:135–136." ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:5 [ 0 => array:3 [ "identificador" => "bib0030" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Talidomida, redescubrir un viejo fármaco" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "J.M. Casanova Seuma" 1 => "M. Baradad Brusau" 2 => "R.M. Martí Laborda" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Piel" "fecha" => "2003" "volumen" => "18" "paginaInicial" => "446" "paginaFinal" => "458" ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0035" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Thalidomide-induced amenorrhea: case report and literature review" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "S.P. Dharia" 1 => "M.P. Steinkampf" 2 => "C. Cater" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.fertnstert.2003.12.038" "Revista" => array:6 [ "tituloSerie" => "Fertil Steril" "fecha" => "2004" "volumen" => "82" "paginaInicial" => "460" "paginaFinal" => "462" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15302302" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0040" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/000823/WC500037054.pdf" "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Evaluation of medicines for human use. EMEA/176582/2008. Assessment report for thalidomide pharmion" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "European Medicines Agency" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Libro" => array:3 [ "fecha" => "2008" "editorial" => "EMA" "editorialLocalizacion" => "London" ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0045" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Thalidomide-induced amenorrhoea: two cases" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "T. Passeron" 1 => "J.P. Lacour" 2 => "D. Murr" 3 => "J.P. Ortonne" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Br J Dermatol" "fecha" => "2001" "volumen" => "144" "paginaInicial" => "1292" "paginaFinal" => "1293" ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0050" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Ovarian function in female patients with multibacillary leprosy" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "K. Neena" 1 => "A.C. Ammini" 2 => "M. Singh" 3 => "R.K. Pandhi" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Int J Lepr Other Mycobact Dis" "fecha" => "2003" "volumen" => "71" "paginaInicial" => "101" "paginaFinal" => "105" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12914132" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/23870206/0000014900000003/v1_201708260033/S2387020617304485/v1_201708260033/en/main.assets" "Apartado" => array:4 [ "identificador" => "43309" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Letters to the Editor" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/23870206/0000014900000003/v1_201708260033/S2387020617304485/v1_201708260033/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2387020617304485?idApp=UINPBA00004N"]

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Vol. 149. Issue 3.

Pages 135-136 (August 2017)

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