Timing is everything

The flow of time is something fundamental in a woman’s life. This particularly applies to the complex and wonderful function of reproductive hormones. From the beginning of life itself, the embryo develops under subsequent waves of cell, tissue and organ differentiation and these phenomena are tightly controlled by dynamically changing amounts of sex steroid hormones. After birth, pubertal development is the paramount example of how important is time for the effect of steroid hormones. The increase in the pulsatility of the gonadotropin-releasing hormone pulse generator, leading to more frequent releases of gonadotropins from the pituitary gland, and the enhanced response to gonadotropins from the follicles are awesome and unique processes in Nature. This perfect machinery is what Nature has developed to plan the right moment for a woman to become pregnant – the single most precious event for the survival of the species – as well as to chart those moments in a woman’s life when pregnancy should be avoided so to protect the most precious individual, the mother. This is not trivial. This is what largely allowed our survival and evolutionary success. Chronobiology is a distinct discipline in the vast field of reproductive medicine that was created specifically to describe the fact that a woman’s body is possibly the most amazing chronograph that any Swiss craftsman could have ever manufactured. Distinguished scientists and clinicians have devoted lifetimes of relentless effort to understand the complexity of the dynamics of reproductive endocrinology, and the results of these pioneers are reflected in our current ability to understand and treat conditions where the gears of this complex apparatus derange and fail in women. Thus time is a key factor to be considered by a clinician dedicated to women’s health. How could we provide effective hormonal contraception if not considering the correct timing for administration of the steroids? How could we achieve ovulation induction if not through a profound understanding of how and when to provide gonadotropins? How could we even treat common conditions such as luteal insufficiency if not through a correct timing of progestogens administration? Yet, why is it so hard in menopausal medicine to get through the simple and straightforward concept that the administration of steroid hormones cannot result in consistent effects if not performed in the right way? We have gone through years of hazy vision in reproductive medicine. Years when even simple clinical concepts have been disregarded in the name of a modern vision of medicine based on objectivity and statistics. The introduction of evidence-based medicine has certainly been a major advancement in the way we perform research, but the human organism cannot always be standardized and the possibility to apply statistical boundaries to clinical trials in reproductive endocrinology cannot be done without a profound understanding of reproductive endocrinology itself. This is why major clinical trials in postmenopausal women have generated such appalling results, and why we have all been talking endlessly about statistics and trial designs when we should get back to endocrinology and to women. What stuns me most is the apparent lack of dismay worldwide about the practice that has been envisioned by the Women’s Health Initiative (WHI) trial [1,2]. During the past four years little has been written or said on the complete nonsense of administering estrogens with or without progestins in a single dose, by a sole route of administration and, mostly, at any age after menopause.