Sequential classification of endocrine stages during reproductive aging in women: the FREEDOM study*

In Brief Objective: Reproductive aging involves complex endocrine changes affecting women's fertility, health, and well-being; however, understanding of the specific changes involved is limited by the lack of detailed quantitative studies. We undertook a thorough study with the aim of characterizing the different endocrine stages involved in female reproductive aging. Design: FREEDOM is a cohort study designed to determine the endocrine changes during reproductive aging in women. Here, we ascertained the different endocrine patterns in a representative population and developed a staging system. In this study, 112 women aged 30 to 58 years collected daily urine samples over a 6- to 18-month period and recorded their menstrual periods. A total of 36,786 samples were analyzed for follicle-stimulating hormone (FSH), luteinizing hormone, estrone 3-glucuronide, and pregnanediol 3-glucuronide. Results: A classification of five sequential endocrine stages of reproductive aging was developed: stage 1, regular menstrual cycles with mean initial (day 1-5) FSH less than 5 IU/L; stage 2, regular cycles with FSH greater than 5 IU/L; stage 3, menstrual irregularity (with the appearance of “delayed-response cycles”); stage 4, acyclical ovarian activity with no evidence of ovulation and luteinization; and stage 5, ovarian quiescence and persistently raised gonadotropins. Distinct hormonal characteristics during the follicular and luteal phase were noted at each stage. Conclusion: This classification provides a detailed insight into the endocrinology of reproductive aging in women that could be useful for both clinical guidance and personal health care. A classification of five sequential endocrine stages involved in reproductive aging is proposed. The categories define the overall process starting with elevation in the levels of follicle-stimulating hormone, followed by the emergence of menstrual irregularity with two distinct types of menstrual cycles. Just before menopause, there is a stage with erratic ovarian activity but no signs of ovulation.