RESUMEN
BACKGROUND: Premature ovarian insufficiency (POI), often and misleadingly referred to as 'premature menopause', is defined as a loss of ovarian activity before the age of 40 years and is characterized by irregular or absent periods and reduced fertility. Symptoms include those associated with the natural menopause (night sweats and vaginal dryness), and with the long-term adverse effects of estrogen deficiency (osteoporosis and cardiovascular disease): the latter is believed to explain the shorter life expectancy associated with POI. OBJECTIVE AND RATIONALE: The objective of the current review was to collect all relevant studies supporting recommendations on the indications, treatment options, and risks of hormone replacement therapy (HRT) (estrogen, progestogens and androgens) for women with POI. SEARCH METHODS: The current review was written based on the best available evidence on the topic collected for the recently published ESHRE guideline on the management of women with POI. PUBMED/MEDLINE and the Cochrane library were searched in a stepwise approach. Relevant references were summarized in evidence tables, with assessment of the quality. OUTCOMES: HRT is strongly recommended for women with POI, mainly for vasomotor and genito-urinary symptom relief. In addition, HRT has been shown to have a role in bone protection and probably also in primary prevention of cardiovascular disease. There is little evidence on the optimal type, regimen and dose of HRT; patient preference for route and method of administration of each component of HRT must be considered when prescribing, as should contraceptive needs. In women with POI, physiological replacement of estrogen (and progesterone) is essential for their health, and the controversies that surround the use of HRT in postmenopausal women do not apply. LIMITATIONS REASONS FOR CAUTION: N/A. WIDER IMPLICATIONS: New areas of study on HRT for women with POI should focus on life expectancy, quality of life and neurological function. Furthermore, randomized controlled trials comparing transdermal estradiol with oral estrogens with regard to efficacy, patient satisfaction and side effects are urgently needed. STUDY FUNDING/COMPETING INTERESTS: The authors received no funding for the review. The costs for the development of the ESHRE guideline were covered by ESHRE. The authors have no conflicts of interest to disclose.
RESUMEN
OBJECTIVE: To evaluate the significance of NR5A1 mutations in a large, well-phenotyped cohort of women with primary ovarian insufficiency (POI). Mutations in the NR5A1 gene (SF-1) were previously described in disorders of sexual development and adrenal insufficiency. Recently, a high frequency of NR5A1 gene mutations was reported in a small group of women with POI. DESIGN: Cross-sectional cohort study. SETTING: University hospital. PATIENT(S): Well-phenotyped women (n = 386) with secondary amenorrhea and diagnosed with POI, including women with familial POI (n = 77). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The entire coding region and splice sites of the NR5A1 gene were PCR-amplified and sequenced. The pathogenicity of identified mutations was predicted in silico by assessing Align-GVGD class and Grantham score. RESULT(S): Sequencing was successful in 356 patients with POI. In total, 9 mutations were identified in 10 patients. Five of these mutations concerned novel nonconservative mutations occurring in 5 patients. Prediction of effect on protein function showed low to intermediate pathogenicity for all nonconservative mutations. The overall NR5A1 gene mutation rate was 1.4%. CONCLUSION(S): The current study demonstrates that mutations in the NR5A1 gene are rare in women with POI. Primary ovarian insufficiency remains unexplained in the great majority of patients; therefore, continued efforts are needed to elucidate its underlying genetic factors.
Asunto(s)
Mutación Puntual/genética , Insuficiencia Ovárica Primaria/genética , Factor Esteroidogénico 1/genética , Adolescente , Adulto , Estudios Transversales , Femenino , Predisposición Genética a la Enfermedad/epidemiología , Predisposición Genética a la Enfermedad/genética , Pruebas Genéticas , Humanos , Persona de Mediana Edad , Fenotipo , Insuficiencia Ovárica Primaria/epidemiología , Sitios de Empalme de ARN/genética , Adulto JovenRESUMEN
OBJECTIVE: The measurement of serum testosterone in women is challenging due to lack of trueness, precision, and sensitivity of various available testosterone assays. Accurate assessment of testosterone in women is crucial especially in conditions associated with alleged over- or under-production of testosterone, such as in polycystic ovary syndrome (PCOS) or primary ovarian insufficiency (POI). The aim of this study was to measure and compare androgen concentrations in women with PCOS, POI, and female controls and to evaluate the performance of extraction RIA and liquid chromatography-tandem mass spectrometry (LC-MS/MS) in these women. DESIGN: Cross-sectional study. METHODS: Carefully phenotyped women with POI (n=208) or PCOS (n=200) and 45 healthy, regularly cyclic female controls were included. Method comparison analyses were performed for total testosterone, androstenedione (AD), and DHEA, as measured by LC-MS/MS and extraction RIA. RESULTS: All androgen levels were significantly elevated in women with PCOS compared with POI patients (P<0.05) and controls (P<0.05). Women with POI presented with similar androgen concentrations as controls, except for AD. Compared with measurements by extraction RIA, testosterone, DHEA, and AD concentrations measured by LC-MS/MS were systematically lower. However, using extraction RIA and LC-MS/MS, testosterone, DHEA, and AD measurements were shown to have good agreement as assessed by Bland-Altman analysis and intraclass correlation coefficient: 0.95 (95% confidence interval 0.94-0.91), 0.83 (0.79-0.86), and 0.96 (0.95-0.97) respectively. CONCLUSIONS: LC-MS/MS, compared with a labor-intensive extraction RIA, shows good precision, sensitivity, and high accuracy for measuring female testosterone, DHEA, and AD concentrations under various clinical conditions. LC-MS/MS, therefore, represents a convenient and reliable assay for both clinical and research purposes, where androgen measurement in women is required.
Asunto(s)
Andrógenos/sangre , Espectrometría de Masas en Tándem/normas , Adolescente , Adulto , Biomarcadores/sangre , Cromatografía Liquida/métodos , Cromatografía Liquida/normas , Estudios Transversales , Femenino , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Radioinmunoensayo/métodos , Radioinmunoensayo/normas , Distribución Aleatoria , Espectrometría de Masas en Tándem/métodos , Adulto JovenRESUMEN
CONTEXT: In young women, some treatments for cancer or other conditions (such as sickle cell anemia) may give rise to primary ovarian insufficiency. Ovarian transplantation is one of the available options for fertility preservation, with highly variable pregnancy rates. OBJECTIVE: The objective of the study was to investigate markers of ovarian reserve and ovarian function in women up to 7 yr after orthotopic ovarian transplantation. Secondary objectives were to assess the relationship between markers of ovarian reserve and pregnancy rate along with the duration of ovarian function. DESIGN: This was a prospective cohort study in 10 women, with a mean follow-up of 2.5 yr. SETTING: The study was conducted at a university hospital in Brussels, Belgium. PATIENTS: Patients included 10 women who were about to receive or had previously received gonadotoxic treatment. In seven women cryopreservation of ovarian tissue was performed before starting treatment. Subsequently autografts were orthotopically transplanted in these women. Three women, who had already developed primary ovarian insufficiency due to treatment, underwent orthotopic transplantation of ovarian allograft tissue originating from their human leukocyte antigen-compatible sisters. MAIN OUTCOME MEASURES: Serum concentrations of FSH, LH, estradiol, inhibin B, and anti-Müllerian hormone (AMH) were measured. RESULTS: On average, first menses took place after 4.7 months. Duration of graft functioning varied from 2 to more than 60 months. FSH concentrations remained elevated, whereas estradiol levels normalized and AMH was low to undetectable. Inhibin B varied among women and was not associated with the duration of ovarian function (hazard ratio 0.966, 95% confidence interval 0.881-1.059). Two spontaneous pregnancies occurred. Endocrine characteristics were not significantly different in these women. CONCLUSIONS: Low AMH and inhibin B concentrations may suggest decreased ovarian reserve in women after ovarian transplantation. AMH and inhibin B levels may not be associated with the duration of ovarian graft function or probability to achieve a pregnancy.
Asunto(s)
Antineoplásicos/efectos adversos , Biomarcadores/análisis , Ovario/fisiología , Ovario/trasplante , Insuficiencia Ovárica Primaria/inducido químicamente , Insuficiencia Ovárica Primaria/rehabilitación , Adulto , Hormona Antimülleriana/análisis , Hormona Antimülleriana/sangre , Criopreservación , Estradiol/análisis , Estradiol/sangre , Femenino , Hormona Folículo Estimulante/análisis , Hormona Folículo Estimulante/sangre , Estudios de Seguimiento , Humanos , Infertilidad Femenina/sangre , Infertilidad Femenina/diagnóstico , Infertilidad Femenina/prevención & control , Inhibinas/análisis , Inhibinas/sangre , Valor Predictivo de las Pruebas , Embarazo , Insuficiencia Ovárica Primaria/fisiopatología , Insuficiencia Ovárica Primaria/terapia , Trasplante Heterotópico , Adulto JovenRESUMEN
OBJECTIVE: Premature ovarian failure (POF) is characterized by secondary amenorrhea before the age of 40 years, along with repeated increased follicle-stimulating hormone and low estrogen concentrations. POF is considered a complex genetic disease with a familial presentation in 12% to 50% of cases. POF may originate from different genes and various gene-environment interactions. The aim of this study was to identify possible differences in phenotype comparing women with familial and women with sporadic POF. METHODS: A multicenter study was initiated in the Netherlands using standardized phenotyping. For each woman, medical history, menstrual cycle, and fertility and smoking status were assessed and a standardized examination was performed. Based on a detailed three-generation family history, women were identified as having either familial (defined as having at least one relative with POF) or sporadic POF. RESULTS: A total of 58 familial cases and 142 sporadic cases of POF were identified. Maternal age at menopause was significantly lower in the women with familial compared with the women with sporadic POF (41.0 +/- 7.5 and 49.7 +/- 2.6 y, respectively; P < 0.001). Sex hormone-binding globulin concentration was significantly higher in the women with familial than in the women with sporadic POF (73.6 +/- 37.1 and 55.2 +/- 26.9 nmol/L, respectively; P = 0.002). All other characteristics, such as parity, bone mineral density, and serum follicle-stimulating hormone and lipid levels were similar, as was the incidence of autoimmunity and cytogenetic abnormalities. CONCLUSIONS: Familial and sporadic POF do not differ in phenotype except for maternal menopause age and sex hormone-binding globulin concentration. Future studies are needed to unravel the genotype-phenotype interactions in POF.