Post NICE Guidelines: could precision prescribing of estrogen be achieved?

Keywords:

• NICE Guidelines
• menopause
• management
• estrogen
• prescribing

The publication of the NICE guidelines on the management of the menopause¹ drew a line under 15 years of confusion created by the publication of the first analysis of the Women's Health Initiative (WHI) study. These guidelines, based on extensive reviews of the safety data on postmenopausal hormone replacement therapy (HRT) and made accessible to the general public, will encourage more women to discuss starting HRT with their primary health-care providers. A new generation of women with estrogen deficiency symptoms has arrived on the clinical scene; they have a different benchmark for quality of life compared to their seniors, are more assertive, greatly enabled by the internet, and are asking serious questions on how to effectively manage their menopause. Increased longevity is a major factor for this shift in interest, with increasing concerns about age-related morbidities and ways to reduce such risks. It is this new generation of women at the age of the menopause that is expected to work till the age of 70 before they qualify for the state pension in the United Kingdom, for example. The diagnosis of the menopause is easy and so is its treatment, which, in contrast to many areas of clinical practice, can make a great difference to the mental, social and physical functioning of the symptomatic woman. In this article, I shall try to address individualization of therapy in the light of the variation in the response to estrogen. I shall avoid the progesterone/progestins and progestogens as they are a much more complicated issue than estrogen.

Estrogens are simply ligands that specifically activate members (estrogen receptors α and β) of the family of transactivation proteins that regulate DNA transcription. Estrogen is an essential part of cell biology that has survived 2 billion years of evolution since it was first manufactured by bread mold through an aromatase-dependent pathway. Further, it is endowed with the regulation of reproductive function. In physiological terms, it promotes cell homeostasis and is an essential part of the DNA repair mechanism. These features attest, in principle, to the safety of estrogen.

In the evolution of HRT and over the last four decades, an extensive body of literature has described the tissue homeostatic effects of estrogen and extended the observations to the reduction, or postponement, of age-related morbidities. All these thoughts were carefully balanced against the potential for increasing the risk of developing breast cancer. The clinical enthusiasm combined with the commercial interest in providing women with a primary preventative drug against cardiovascular disease resulted in the launch of the WHI studies. Without getting into any argument about its series of publications, the WHI proved, in the randomized clinical trial setting, the long-awaited fracture-preventing data of estrogen and that estrogen-only therapy, despite it being an equilin-based preparation in this study, is breast cancer risk-neutral. However, what concerns the majority of women in daily clinical practice who request estrogen therapy is the severity of their symptoms and, as a result, their undermined quality of life. The benchmark for successful treatment, therefore, should aim at the abolition, not just amelioration, of these symptoms.

Individualizing treatment is not a new concept and has been frequently advocated in the field of HRT. But what does it mean exactly? Clinicians who follow up their patients and assess their progress on treatment know only too well that a simple prescription of an estrogen preparation does not cure more than half of these women. There are the successfully cured responders, poor responders, non-responders and those who may or may not respond but with severe adverse effects. The pragmatic approach has been to vary the dose or to change the route of administration but this does not mean a linear relationship with response or with the development of adverse effects for that matter. The development of adverse drug reactions and/or inadequate response to a given dose of estrogen, for example, create anxieties among women and their prescribers, resulting in cessation of medications as a 'safe' option or adding an 'antidepressant' in the management of residual symptoms.

In the days when HRT prescribing was very popular, a variety of estrogen preparations were available on the market, ranging from the transdermal patches and gel preparations, nasal sprays, vaginal rings and creams, pellets for subcutaneous implants and a variety of tablets. The latter included the micronized estradiol, its valerated salt, the hemihydrate salt, estrone sulfate and estriol tablets as well as the conjugated equine estrogen. That constellation of estrogen preparations reflected different types of responders and offered therapists a greater flexibility in management. The current spectrum of estrogen preparations has massively shrunk as many hormone-manufacturing companies have either stopped production or have been taken over by conglomerates that do not identify their business plans with the low profit margin of estrogen preparations. This is also complicated by the simplistic views held by the regulatory authorities and the majority of doctors that all these preparations are essentially the same and the only difference one can make is to vary the dose. In general, there is little appreciation of the subtle differences between preparations and the vast spectrum of response among treated women with each single estrogen preparation when the aim is the complete abolition of vasomotor symptoms, for example. Such responses, including palpitations, low moods or fluid retention, can be met with one estradiol preparation but not the other and regardless of route of administration.

The pharmacological principles that underlie the response to estrogen include its effective dose, its residual metabolites, the overall impact on receptor action and whether the serum versus cellular concentrations are the final arbiter in yielding a clinical effect. The objective measurements of estrogen effect in postmenopausal women are limited to serum estradiol level, sex hormone binding globulin and vaginal cytology, but none of these is specific enough to make a judgement in cases of unexpected clinical response. A large body of data has been published on the molecular mechanisms involved in estrogen action, the role of the two nuclear estrogen receptors, and the fast effect of binding the membrane-bound estrogen receptor; it remains that the practical utility of these data is limited at present.

Incomplete symptom control with a high dose of estrogen but with severe mastalgia and estradiol levels, sometimes even below the laboratory detection levels, is not an uncommon outcome in a busy menopause clinic, and altering the route of administration or changing the type of oral preparation may not be enough to resolve the clinical picture.

Endogenous estrogen as well as its exogenous administration are subject to extensive oxido-reduction reactions, regulated by the P450 enzymes, at 2, 4, 11, 16 and 17 positions. This is followed by sulfation, glucoronidation and catechol methylation in various proportions in different women. The concentration pattern of these metabolites is different between oral and parenteral routes of administration, is altered by the dose of estrogen, and exhibits wide inter-individual and racial variations. The P450 enzymes (CYP enzymes) and their isoforms are differentially distributed in cell and tissue context with marked polymorphisms. Hence, the impact of these metabolites on a given outcome is different among women – the development of mastalgia, headaches or irritability, for example. These metabolites are conventionally compared to the binding affinity of 17β-estradiol to its cognate receptors and are considered 'weak' ligands. However, the relative concentration of these metabolites and that of 17β-estradiol as well as the activities of the relevant CYP enzymes and isoforms will govern the net effects of these metabolites on the net outcome of 17β-estradiol in a given cell or tissue and ultimately the clinical response. Escalation of the oral dose of estrogen may not necessarily improve symptom control and can aggravate the adverse effects, but the addition of a transdermal estradiol preparation to the lower oral dose may provide the answer. The rate of absorption may also affect symptom control such as the different response to transdermal patches compared to gels. But these attempts at optimization of therapy are simply trials and errors, which were nurtured in the past by the large variety of estrogen preparations then available.

Individualization of estrogen therapy is therefore the ability of the clinician to provide each woman requesting treatment an effective dose and route of administration with minimal adverse effects that account for variations in absorption, distribution, metabolism and elimination, based on laboratory tests of correlations with her genetic make-up. Pharmacogenomics may well help to develop such promise.

The NICE guidelines have been published at a time when investment in research into women's health has evaporated, not only because of desertion of commercial money but fundamentally because the funding in this area of research is not attractive for voters and, indeed, many opinion leaders in those policy-making circles believe that the menopause and its associated symptoms are women's destiny and they have to cope with it.

In the era of post-NICE guidelines, women and prescribers are assured to an unprecedented level of confidence in the safety of postmenopausal estrogen therapy, particularly after surgical menopause. In order to facilitate the continuation of this effective therapy that cures symptoms and promotes quality of life, a scientific emphasis is necessary that translates into clinical practice in individualization of treatment. To achieve this, we have to re-focus our research efforts to better understand the physiology of estradiol, both individually and in the context of its co-existing metabolites and the protein signatures and enzymatic activities of the handling enzymes. This will be the foundation of more precise assessment of the pharmacological handling of exogenously administered hormones. The big question remains as to who will fund this program? The women themselves, perhaps?