Utilidad clínica de la medición de la hormona antimülleriana en las mujeres / Clinical utility of the measurement of the Anti-müllerian hormone in women

Resumen: la hormona antimülleriana es una glicoproteína homodimérica perteneciente a la superfamilia del factor de crecimiento transformantes beta (TGF-ß). Esta hormona desempeña un papel fundamental en la regresión de los conductos müllerianos en el embrión masculino. En los niños se produce en los testículos, por las células de Sertoli, hasta la pubertad y a partir de allí disminuye lentamente a valores residuales por el resto de la vida. En las mujeres la hormona antimülleriana es secretada por las células de la granulosa de pequeños folículos en el ovario, donde sus niveles reflejan con exactitud la reserva folicular ovárica. Por tal motivo, esta hormona es considerada un marcador extremadamente sensible del envejecimiento ovárico y una herramienta valiosa en el diagnóstico y el reconocimiento de la recurrencia de tumores de células de la granulosa. La evaluación de la hormona antimülleriana también es de importancia clínica en la predicción de la respuesta ovárica, el cese de la función ovárica y la reproducción asistida. Además, puede servir como marcador diagnóstico del síndrome de ovario poliquístico, en los casos en que el examen ultrasonográfico no sea posible de realizar. Finalmente, la medición de los niveles séricos de la hormona antimülleriana, durante la vida reproductiva de la mujer, representa una herramienta ideal para la evaluación de la reserva folicular ovárica. En esta revisión se presenta el rol fisiológico de la hormona antimülleriana en las mujeres, al igual que las principales utilidades clínicas de su medición y las pruebas de laboratorio disponibles para este fin. (AU)

Abstract: Anti-mullerian hormone is a homodimeric glycoprotein belonging to the transforming growth factor beta (TGF-ß) super family. Anti-mullerian hormone plays a fundamental role in the regression of mullerian ducts in male embryo. In boys, it is produced by Sertoli cells of the testes until puberty where slowly decreases to residual values for the rest of the life. In female, it is secreted by granulosa cells of small follicles in the ovary where their levels accurately reflect the ovarian follicular reserve. Therefore, anti-mullerian hormone has been considered as extremely sensitive marker of ovarian aging and a valuable tool in the diagnosis and the recognition of recurrence of granulosa cell tumor. Anti-mullerian hormone evaluation is also of clinical importance in predicting of ovarian responsiveness, ovarian function cessation, and in assisted reproduction. In addition, anti-mullerian hormone could be a diagnostic marker of polycystic ovary syndrome in cases in which ultrasonographic examination is not possible. Finally, the measurement of serum anti-mullerian hormone levels during woman's reproductive life represents an ideal tool for the assessment of the ovarian follicular reserve. This review presents the physiological role of anti-mullerian hormone in women, as well as the main clinical benefits of its measurement and the laboratory tests available for this purpose. (AU)

La hormona antimülleriana como marcador de función ovárica / Anti-Müllerian hormone as a marker of ovarian function

Por décadas, el significado clínico de la hormona antimülleriana (HAM) ha estado limitado a su papel crítico en el desarrollo sexual fetal. Sin embargo, en los últimos 20 años esta ha surgido también como marcador de función ovárica. La HAM tiene funciones específicas como regulador del crecimiento folicular, desempeñando su papel como señal de retroalimentación negativa. Jugaría un papel importante tanto en la regulación del número de folículos en crecimiento (inhibiendo el reclutamiento), como en su selección para ser ovulados (inhibiendo a FSH). La HAM es sintetizada como una pre-prohormona. En el citoplasma cada monómero es clivado generando un fragmento N-terminal: 110 KDa (región pro) y otro C-terminal: 25 KDa (región madura o nativa), unidos en forma no covalente por 2 puentes disulfuro. El dominio C-terminal es el bioactivo, uniéndose al receptor, pero necesita del fragmento N-terminal para desencadenar respuesta biológica. En circulación podemos encontrar una mezcla de la forma pro-HAM y del complejo C-terminal/N-terminal, que serían medidos por los ensayos disponibles. Distintos autores han demostrado que la HAM es un marcador precoz de la disminución y agotamiento de la reserva ovárica. Muestra una estrecha correlación con la reserva folicular y la capacidad reproductiva, más que la FSH y el estradiol. La revisión realizada no deja lugar a dudas sobre la utilidad de la HAM en la etapa fértil. Ha mostrado ser una excelente herramienta para caracterizar pobres respondedoras en los procedimientos de fertilización asistida, alertar precozmente en mujeres jóvenes sobre reserva ovárica baja, en relación con su edad cronológica y expresar un número de folículos en crecimiento elevado, como en síndrome de ovario poliquístico, para evitar una hiperestimulación ovárica. El creciente número de pacientes que decidieron retrasar su maternidad y su papel en la fisiología ovárica han posibilitado que la HAM integre hoy la evaluación de mujeres con alteraciones de la fertilidad.

For many years, the clinical significance of the anti-Müllerian hormone (AMH) was limited to its critical role in foetal sexual development. However, in the last 20 years it has also emerged as a marker of ovarian function. AMH has specific functions as a regulator of follicular growth, playing its role as negative feedback signal. It may also play an important role in the regulation of the number of growing follicles (inhibiting the recruitment) as well as in their selection to be ovulated (inhibiting FSH). AMH is synthesised as a pre-pro-hormone. In the cytoplasm each monomer is cleaved, generating one N-terminal fragment: 110 KDa (pro region) and another C-terminal fragment: 25 KDa, non-covalently bound by two disulphide bridges. The C-terminal domain is bioactive, binding to the receptor, but requires the N-terminal fragment to trigger a biological response. A mixture of pro-AMH complex and C-terminal/N-terminal complex can be found in the bloodstream, which can be measured by the assays available. Several authors have shown that AMH is an early marker of the decrease and depletion of ovarian reserve. It shows a close correlation with follicular reserve and reproductive capacity more than FSH and oestradiol. This review leaves no doubt about the usefulness of AMH in the fertile phase. It has proven to be an excellent tool in characterising poor responders in assisted reproduction procedures, as an early alert in young women of a low ovarian reserve in relation to their chronological age, as well as in expressing a number of follicles in high growth, as in polycystic ovary syndrome, to avoid ovarian hyperstimulation. The growing number of patients who have decided to delay motherhood and the role of AMH in ovarian physiology has led it to an integral part of the assessment of women with impaired fertility.

Tratamento com andrógenos como possibilidade de melhoria do prognóstico reprodutivo em mulheres com envelhecimento ovariano / Treatment with androgens as a possibility to improve the reproductive outcome of women with ovarian aging

Justificativa: A resposta ao estímulo ovariano é uma peça-chave na reprodução assistida. Apesar dos recentes avanços das técnicas, pacientes com baixa reserva ovariana apresentam mau prognóstico e representam um desafio na medicina reprodutiva. Objetivo: Propor estratégia de melhoria do prognóstico reprodutivo em mulheres com idades superiores a 38 anos ou jovens com baixa contagem de folículos antrais, por meio do uso de testosterona previamente ao estímulo ovariano. Material e métodos: Levantamento de dados da literatura científica na área da medicina reprodutiva. Resultados e conclusões: O uso de androgênios em fases que antecedem a estimulação ovariana em ciclos de fertilização in vitro parece ser ótima ferramenta de melhoria da resposta à estimulação oocitária controlada em pacientes com mais de 38 anos ou com reserva ovariana diminuída. Melhora tanto a quantidade quanto a qualidade oocitária e aumenta as taxas de gestação e de nascido vivos.

Justification: The response to ovarian stimulation is a keyelement in assisted reproduction (AR). Despite recent advances in the techniques, patients with low ovarian reserve havepoor prognosis and represent a challenge in reproductive medicine.Objective: To propose a strategy to improve reproductive prognosis of women older than 38years or young women with low antral follicle count, through the use of testosterone prior to ovarian stimulus.Material and methods: Survey data from the scientific literature in the field of reproductive medicine. Results and conclusions: The use of androgens in stages preceding ovarian stimulation in IVF cycles seems to be great tool for improving oocyte response in oocyte controlled stimulation of patients older than 38 years or with diminished ovarian reserve, improving both quantityand quality of oocytes and increasing rates of pregnancy and live-born.

Influence of aging on expression of FSHR mRNA in human ovary / 대한산부인과학회잡지

FSH is the central hormone for the regulation of ovarian function and acts by binding with specific receptor, FSHR, which is one of the G-protein coupled receptor family. The aging of ovary decreases the number and the activity of follicle, which results in the increase of FSH by reduction of inhibin and estrogen. The study on FSH level and FSHR mRNA expression in the ovary of perimenopausal women is the crucial step for the understanding of the menopausal mechanism.We studied FSHR mRNA expression of ovarian follicle by using in situ hybridization and QC RT-PCR. The fresh ovarian tissues and blood samples were obtained from premenopausal women in mid-follicular stage and postmenopausal women. The experimental samples were grouped as below 40 years old women, 40-44 years old ones, 45-49 years old ones, 50-54 years old ones, and postmenopausal women as negative control. To localize FSHR transcripts by in situ hybridization, we synthesized digoxigenin-labelled ssRNA probe (about 800 bp) and measured the degree of staining as 0, 1+, 2+ in the primary follicles which were independent to FSH effect. To do QC RT-PCR, we synthesized oligonucleotide primers (antisense: 5-GGCCCTGCTCCTGG- TCTCTTTG-3, sense: 3-AACAGCGGGAGTACCTTCGG-5) to form the 799 bp sized PCR products. We also synthesized 149 bp deleted DNA competitor by site-directed mutagenesis and then calculated the relative amount of target FSHR mRNA by comparing with competitor after PCR.There were significant reverse relationships between follicular number and aging (r=-0.934, P=0.01), and FSH level (r=-0.713, P<0.001). The similar amount of FSHR mRNA was expressed in the group of below 40 years by in situ hybridization. In the groups of above 40 years, the FSHR mRNA expression decreased progressively according to aging (r=-0.744, P<0.001) and FSH level (r=-0.771, P<0.001). But we could not find FSHR mRNA expression in menopausal ovaries. The amount of follicular FSHR mRNA was measured as 840.00+/-516.29 for the below 40 years group, 240.00+/-154.91 for the 40-44 years group, 40.00+/-21.90 for the 45-49 years group, 6.06+/-4.13 for the 50-54 years group, and 0.48+/-0.00 fg in the postmenopausal ovary. The amount of FSHR mRNA decreased with ovarian aging (r=-0.857, P<0.001) and FSH level (r=-0.771, P<0.001).These results demonstrate that the gradual increase of FSH and the decrease of FSHR mRNA expression in older than 40 years women are related to the changes of sex hormones. However the gradual decrease of the FSHR mRNA expression in the primary follicle may be due to the follicular aging itself. Therefore the menopausal transition already starts at the beginning of 40 years and one of the major cause of the menopause may be the reduction of FSHR mRNA expression followed the decrease of ovarian response to gonadotropins. The further studies should be required to elucidate the underlying mechanism and the associated factors of menopause.