Abstract
“In optimizing individualized sequential combined HRT, one aims for an adequate estrogen dose that cures menopausal symptoms in combination with the cyclical sequential progesterone, or progestagens, using the lowest effective dose for a short duration each month that ensures regular bleeding.”
The menopause is a natural event and marks the end of reproductive function. The diagnosis of estrogen deficiency symptoms is easy and so is the required treatment. HRT is just what it means – the replacement of missing hormones. Women's trust in the use of HRT was shattered in July 2002 when the world media disclosed the ‘consequences’ of treating menopausal women with HRT. The lay media dealt with the findings and sought specialists' opinion even before the medical journal concerned published the data. The resulting confusion drove the majority of women to discontinue a much-suited treatment that maintained their quality of life. The data were criticized due to the less than careful analysis with questionable principles adopted for recruitment into the trial. A fixed combination of estrogen and a progestagen was given to women between the age of 50 and 79 years old, a fifth of whom were 70–79 years. The recruited population was a mixture of past users of HRT, as well as treatment-naive women. Furthermore, some women enrolled into the trial were asymptomatic, as well as those who suffered symptoms of estrogen deficiency. The expectations of the steering committee were simplistically optimistic in that a single preparation would be used by all women and ‘one size fits all’ would be at hand to cure all ills.
Evolution of HRT regimens
Estrogen deficiency symptoms were successfully treated with unopposed estrogen in women with intact uteri until 1975, when publications suggested that, in addition to irregular bleeding, such treatment increased the risks of endometrial hyperplasia and carcinoma [1]. In the UK, adding synthetic progestagen (or a progestin) for 7 days each month was already practiced, albeit not universally, to reduce the incidence of irregular bleeding. (For the rest of this editorial, progestagen(s) will refer to both progestin(s) and progestagen(s).) Formal publications followed to confirm this approach [2]. Further studies attempted to optimize the dose and duration of the progestagen, and suggested that a 12-day treatment during each 28–30-day cycle of continuous estrogen would regulate the withdrawal bleeding and reduce the incidence of endometrial hyperplasia and carcinoma [3,4]. However, unscheduled bleeding on sequential combined HRT and the development of premenstrual tension-like symptoms (e.g., dysphoria, bloatedness and fluid retention) remained a clinical challenge [5,6].
“An appropriately adjusted estrogen regimen cures almost all menopausal symptoms, protects against osteoporosis and, when used in women younger than 60 years, may half the risk of cardiovascular disease … and cognitive impairment…”
The experienced clinician would try to adjust the dose and duration of the progestagen, using the mini-pill, for example, to optimize the regimen for the individual woman and, as such, enhance long-term concordance with HRT. The pharmaceutical market could not cope with this approach since it would be far more profitable to provide a predefined combination package for which a license was granted.
The call on progestagens to resolve the bleeding problem
The re-establishment of a monthly bleed was met with resentment from many women who felt ‘liberated’ from the monthly chore when they reached the menopause. In addition, the health economists viewed the introduction of HRT in postmenopausal women, with its possible unscheduled bleeding leading to further assessment and gynecological referral, as pressure on resources [7,8]. Given the perceived benignity of progestagens at those times, their utility in continuous dosing with estrogen was promoted as ‘it could only do good to women’ and a new concept was born.
The industry proceeded in earnest to develop continuous combined HRTs (ccHRTs) as non-bleeding regimens. The introduction of ‘bleed-free HRT’ had fulfilled this particular demand of women and made doctors feel better able to manage women without the potential referral for the management of unscheduled bleeding.
“A mounting body of evidence points the finger at continuously added progestagens as the antagonizing factor to the beneficial effects of estrogen.”
Sequential combined HRT was relegated to junior women in the menopause transition and ccHRT became the reward of seniority. The other buzz phrase used to promote ccHRT was the reduction of endometrial hyperplasia and cancer. The sense of satisfaction with this achievement prevailed despite the fact that unscheduled bleeding in women using ccHRT affected more than half of the users during the first 3 months and 20% of women continued to experience irregular bleeding after 6 months of use [9]. Many women discontinued treatment due to progestagen-associated adverse effects, particularly dysphoria and perpetual sense of premenstrual tension.
Several developments followed where the progestagen was administered parentally, including transdermal patches and vaginal rings releasing progestagens, as well as vaginal progesterone cream, but all failed to eliminate the adverse effects of the endometrial protector. Even the levonorgestrel (LNG)-loaded intrauterine contraceptive device is associated with high systemic absorption and corresponding adverse effects. The mean serum LNG level in LNG-loaded intrauterine contraceptive device users is equivalent to the serum levels achieved by two LNG mini-pills daily [10–12].
At the height of HRT popularity, only a third of hysterectomized women (estrogen-only users) or those with intact uteri used the treatment for more than 12 months [13]. This cannot be explained by fear of adverse effects alone, and suitability of a given hormone product and/or its dose deserves serious consideration.
Progestagen use is at fault
The clinical trials and the observational studies published during the last decade pointed to the ‘causal’ relationship of ccHRT with increased risks of breast cancer, stroke, heart attacks and dementia [14]. These estimates were systematically challenged by prominent statisticians worldwide [15–17]. The presumed increased risk of strokes, heart attacks and dementia were not found as exaggerated by the initial reports and were mainly related to old age at initiation of treatment.
The increased risk of breast cancer and that of dementia with ccHRT remained unresolved. The data that have emerged from estrogen-only therapies have clearly indicated that estrogen is not only breast cancer risk neutral, but there were also reduced risks in hysterectomized women. This reduction continued after 10.7 years of follow-up [18]. When comparing the incidence of breast cancer in the placebo arms of WHI trials, it is of note that these women were themselves at a higher risk of developing breast cancer compared with those with intact uteri [14,19]. Unlike the data with ccHRT [20], the incidence of dementia in the WHI estrogen-only study was not statistically significantly different from those on placebo [21]. A mounting body of evidence points the finger at continuously added progestagens as the antagonizing factor to the beneficial effects of estrogen.
Ligand activation of progesterone receptor
Traditional teaching in medicine, particularly in the hormone contraceptives literature, emphasizes the mitogenic and thrombogenic effects of estrogens, although the thrombogenic effect was not found in association with transdermally administered estradiol. Indeed, even the US FDA classified estrogen as a carcinogen. On the other hand, progestagens are depicted as ‘harmless’ therapeutics with their metabolic and cellular effects being largely trivialized.
Cellular synthesis of progesterone receptors (PRs) is a function of a fully activated estrogen receptor. Ligand activation of PR-A and -B accelerates their nuclear depletion through ubiquitination and proteasomal degradation, reduces estrogen receptor synthesis and activates 17β-hydroxysteroid dehydrogenase. The latter accelerates the catabolism and in activation of intracellular estrogen. Hence, the ligand-activated PR exerts the antagonistic effect on endometrial glandular proliferation, but at the same time it induces endometrial stromal proliferation. By contrast, breast glandular proliferation is stimulated under the influence of progesterone and progestagens [22]. Therefore, a continuous antagonistic effect of estrogen action in other tissues may not be as beneficial as seen in the endometrium and may well be harmful.
Progestagens bind other nuclear receptors
Administered progesterone or progestagens activates PR-A and -B to various degrees in a cell and tissue context. As steroidal compounds, their administration results in varying degrees of androgen, glucocorticoid and mineralocorticoid receptors' activation; hence, the recognized adverse effects of the progestagens.
“Longevity has increased so rapidly during the last century and the menopause is considered a mid-life, rather than encl-of-life event. Indeed, women are expected to work for longer and the pension age will soon be raised to 70 years.”
Clinically, a progressively unfolding story is the long-term effect of continuously administered progesterone and its analogs, through glucocorticoid receptor activation, on neurons. Continuous treatment with glucocorticoids reduces neural plasticity and spine formation in hippocampal and nucleus accumbens connections [23–25].
Other effects of continuous exposure to progestagens include a variable degree of adverse effects on glucose and lipids metabolism [26], as well as vascular reactivity [27]. Furthermore, depot progestagens and high progestagen-containing contraceptive pills reduce vaginal immunity [28] and enhance oncogenic transformation of human papilloma virus. One explanation being the interaction of these synthetic compounds with the glucocorticoid receptor response element in the open reading frame of human papilloma virus types 16 and 18 that encode E6 and E7 oncoprotein formation [29].
Quality of life & the menopause
Menopausal symptoms of hot flushes, night sweating, insomnia, panic attacks, depressive moods, emotional lability and loss of libido are inconvenient enough to undermine quality of life. Genitourinary symptoms may develop early in the menopause transition, thus adding to the woman's distress. Longevity has increased so rapidly during the last century and the menopause is considered a mid-life, rather than end-of-life event. Indeed, women are expected to work for longer and the pension age will soon be raised to 70 years. An appropriately adjusted estrogen regimen cures almost all menopausal symptoms, protects against osteoporosis and, when used in women younger than 60 years, may half the risk of cardiovascular disease [30] and cognitive impairment [31].
In women with intact uteri, endometrial protection is required. The woman needs to understand these complicated risk issues through friendly websites and informed consultations, thus enabling her to make informed health choices. Women concerned about the deterioration of their quality of life, if appropriately informed, will accept the re-establishment of withdrawal bleeding as a reasonable trade off for long-term safety of a much-needed HRT. The clinician needs to learn how to confidently manage unscheduled bleeding and learn how to help women make a safe choice in the management of the menopause. In optimizing individualized sequential combined HRT, one aims for an adequate estrogen dose that cures menopausal symptoms in combination with the cyclical sequential progesterone, or progestagens, using the lowest effective dose for a short duration each month that ensures regular bleeding [32]. In adopting this principle with the currently available preparations, the woman is cured of her symptoms, the bleeding pattern becomes more tolerated and the risks of long-term treatment are minimized.