Abstract
In November 1929, clinicians first attempted to develop an ‘ovary stimulating hormone’ extracted from the human placenta for the treatment of symptoms resulting from the menopause. The team at Montreal General Hospital named it ‘Emmenin’ and it had to be purified from the urine of pregnant women to be administered orally. It was later discovered that pregnant mares’ urine could provide an abundant supply of a compound with high estrogenic activity. This conjugated equine estrogen (CEE) was commercially produced as Premarin and made available as an oral estrogenic agent in 1939.
In November 1929, clinicians first attempted to develop an ‘ovary stimulating hormone’ extracted from the human placenta for the treatment of symptoms resulting from the menopause. The team at Montreal General Hospital named it ‘Emmenin’ and it had to be purified from the urine of pregnant women to be administered orally. It was later discovered that pregnant mares’ urine could provide an abundant supply of a compound with high estrogenic activity. This conjugated equine estrogen (CEE) was commercially produced as Premarin and made available as an oral estrogenic agent in 1939.
Premarin still remains commercially available, but since then various other estrogenic compounds have been developed for the management of menopausal symptoms. These include the synthetic estradiol ethynyl estradiol, estradiol, and the synthetic estrogen in Tibolone.
Estradiol is plant derived and has a similar biochemical structure to estradiol released by the human ovary. Estradiol has gradually become the more commonly used estrogen in current MHT preparations with studies showing a more favourable benefit–risk profile with its use over CEE especially when estradiol is administered transdermally. Estradiol is available in oral, transdermal, vaginal preparations as well as subcutaneous implants.
In the late 1970s, the link between unopposed estrogen exposure and endometrial hyperplasia was highlighted and subsequently the use of cyclic or continuous progestogen alongside estrogen became the standard therapy for women with an intact uterus.
The results from the Women’s Health Initiative study (WHI) concluded that the expected benefits of menopausal hormone therapy (MHT) may be outweighed by the risks of breast cancer and stroke. This caused great concern amongst both clinicians and patients alike and has had a negative impact on the uptake and use of MHT that has continued to this day.
This chapter outlines the use of oestrogens and progestogens in MHT.
Estrogen Physiology
The term natural has been used to describe estrogen sourced from plants or animals, but also to describe preparations that have the same chemical structure to human estrogens. The latter consist of estrone (coded E1), 17β-estradiol (E2) and estriol (E3).
17β-estradiol is the most potent naturally occurring estrogen; with estrone (the main estrogen produced in the body after the menopause) being half as active and estriol (main estrogen released during pregnancy) even less active than estrone. Estradiol is available in oral and transdermal delivery systems and as subcutaneous implants for systemic use, as well as preparations for local vaginal administration.
For MHT, 17β-estradiol is commonly administered at oral doses of 0.5–2.0 mg/day, transdermal doses of 25–100 μg/day when administered through transdermal patches or estradiol gel preparations (one to four measures a day) [4]. Bioavailability will differ between women but as a rough estimate 1 mg of oral 17β-estradiol is equivalent to two measures (each measure delivering 0.6 mg) of estradiol gel and 50 μg/day delivered through a patch.
Routes of Administration of Estrogens
Oral Administration
Both estrone and estriol cannot be absorbed through the gastrointestinal tract. Estradiol once ingested orally undergoes rapid conversion to estrone within the intestinal tract. This is further metabolized and conjugated in the liver, via the first-pass liver effect, resulting in glucuronidation of up to 30 per cent of the initial oral dose.
Oral estrogens can be micronized to enhance oral bioavailability and prevent degradation. Micronization describes the process of breaking down the product into very small particles, thereby increasing surface area and speed of absorption. Despite this step, due to first-pass metabolism, approximately only 5 per cent of the oral dose of estradiol becomes available as unchanged estradiol in the circulation and therefore able to exert an estrogenic effect.
Esterification of estradiol aims to improve absorption and bioavailability after oral administration. Following absorption, the esters are cleaved, resulting in the release of endogenous estradiol.
The route of administration of estrogen therapy (ET) impacts upon the risk profile of the medication due to the first-pass liver metabolism associated with oral administration of estradiol. Transdermal ET avoids the first-pass effect through the liver and does not alter coagulation factors and has been shown to have a neutral effect on liver pro-inflammatory markers. Evidence from large observational studies and meta-analyses has shown that transdermal administration of estradiol is unlikely to increase the risk of venous thromboembolism (VTE) above that in non-users of MHT and is associated with a lower risk compared with oral administration of estradiol. This is particularly relevant for women with an increased background risk of VTE including those with raised BMI and increased genetic risk [1]. The latter is discussed in further detail later in this chapter.
Smoking has been shown to increase estrogen clearance from the liver. Consequently, serum concentrations of estrone and estradiol have been found to be lower in smokers when compared to non-smokers following oral administration of estrogen. This difference, however, is not noted with transdermal therapy.
Transdermal Administration
Transdermal estradiol delivery systems currently used in practice include patch and gel preparations. Patches contain estradiol dissolved onto an adhesive matrix. Depending on the system, these patches have to be changed once or twice a week.
Estradiol gel preparations are commonly applied to the skin daily. Absorption occurs within minutes and serum concentrations reach a steady state within a few days.
Vaginal Estrogens
ET is one of the most effective interventions used to manage the symptoms of vaginal atrophy and urogenital ageing [2]. Estrogen increases mucosal proliferation, thus increasing blood supply to the urogenital tissues, and improves vaginal lubrication. ET also restores an acidic tissue pH by increasing lactobacilli dominance within the vaginal flora.
It has been shown that approximately 25–40 per cent of women receiving systemic ET without topical vaginal estrogen replacement continue to experience symptoms related to estrogen deficiency and this is often significantly improved by the addition of topical vaginal estrogens.
Meta-analysis data have shown that ET, in particular vaginal ET, is highly effective in improving symptoms of vaginal atrophy, through the reversal of cytomorphologic changes typically seen with the menopause. Vaginal estrogen has also been shown to have a beneficial effect in managing urinary urge incontinence symptoms as well as for the prevention of recurrent urinary tract infections in postmenopausal women.
Vaginal estrogen delivery preparations include micronized estradiol tablet (Vagifem 10), Estriol cream (Ovestin 0.1 per cent or Gynest 0.01 per cent) and low-dose estradiol-releasing rings made from a silicone elastomer that require replacing every 3 months. All are considered equally effective. In addition, vaginal estrogen preparations are associated with minimal systemic absorption and long-term data with vaginal therapy has shown no adverse effect on endometrial proliferation in follow-up studies ranging from 6 to 24 months with no increase in the risk of endometrial hyperplasia compared with controls. There is therefore no need for concomitant progestogen therapy nor endometrial surveillance in asymptomatic women receiving vaginal estrogen therapy.
When the vaginal mucosa is at its most atrophic, greatest permeability occurs and as the mucosa matures permeability decreases. It is therefore common practice to start administering vaginal estrogens more frequently, initially often given daily for the first 2–3 weeks then continued in maintenance dose commonly given two to three times a week, which can be continued long term.
Vaginal estrogen therapy may be considered in women with a history of hormone-sensitive malignancy particularly those with estrogen receptor negative tumours and in women not receiving aromatase inhibitors after considering the advantages and disadvantages of each case with the patient. This should be weighed up carefully in collaboration with the woman’s oncology team and menopause specialist. This is discussed in further detail elsewhere in this book.
Vaginal moisturizers and lubricants used alone or in conjunction with estrogen therapy may also be considered for the management of vaginal dryness and dyspareunia.
Progestogens
Unopposed systemic ET has been shown to increase the risk of endometrial hyperplasia and endometrial cancer in women with an intact uterus. To counteract this risk, progestogens are used in conjunction with systemic ET. Studies have shown that the protective effect of progestogens used within combined MHT regimens is both dose and duration dependent. There is, therefore, a need to ensure that progestogens administered within both sequential and continuous combined MHT regimens are given in adequate duration and dose.
The primary role of progestogens in MHT is endometrial protection. In sequential MHT regimens and following administration of estrogen, the endometrium develops progesterone receptors. Secretory differentiation occurs once these receptors are exposed to progestogens. Withdrawal of progestogens subsequently results in endometrial shedding and withdrawal bleeding. On the other hand, with continuous combined MHT intake, sustained use of progestogens results in down-regulation of the endometrial estrogen receptors, resulting in an atrophic endometrial state and a thin endometrium. This combination is often referred to as ‘bleed-free’ MHT.
Endometrial protection could be achieved by giving progesterone in the form of micronized progesterone or synthetic progestogens (e.g. dydrogesterone, medroxyprogesterone acetate, norethisterone or levonorgestrel).
In women who had a subtotal hysterectomy, adding progestogen to ET within MHT may be considered if there are concerns that the remnant cervical stump may contain residual endometrial tissue. In clinical practice, this could be assessed by administering sequential MHT for 3 months and if no bleeding is experienced it can be assumed that no significant endometrial tissue is present. Alternatively, if there are concerns that residual endometrial tissue is present in the remnant cervical stump, then a daily intake of progestogen by administering MHT in a continuous combined intake could be considered.
Continuous combined HRT regimens with progestogen may be considered in women following hysterectomy for severe endometriosis. This is discussed in further detail elsewhere in this book. In addition, progestogen replacement should be given as part of MHT in women who have undergone endometrial ablation.
Three classes of progestogens are utilized in MHT:
1. Progesterone derivatives (examples include medroxyprogesterone acetate, megestrol and progesterone).
2. Testosterone derivatives (norethindrone, norethindrone acetate and levonorgestrel).
3. Spironolactone-derived drospirenone.
Synthetic progestogens (also referred to as progestins) are a diverse range of molecules which have an affinity for the progesterone receptors (PR). Progestogens, however, could have an affinity towards other receptors beyond PR and this may result in agonist activity at the glucocorticoid receptors (GR), androgen receptors and mineralocorticoid receptors (MR) and may consequently result in side effects related to stimulation of these receptors.
Progestins intake could result in water retention and weight gain via its activity on the MR and GR receptors and may also affect salt and water retention. MHT containing the progestogen drospirenone as Angeliq may be considered in progestogen-intolerant women as this may be associated with less progestogenic side effects due to its anti-mineralocorticoid activity. Dydrogesterone has been noted to have a more neutral metabolic and side effect profile compared to other synthetic progestogens. These side effect profiles should be considered when counselling women to decide the optimal type of progestin to use within their MHT regimen.
Evidence from large observational studies and case control studies suggests that micronized progesterone and dydrogesterone may be associated with a lower risk of breast cancer and a lower risk of VTE and stroke compared to that noted with other progestogens.
Oral Administration
After oral administration all progestogens are rapidly metabolized in the gastrointestinal tract and liver, producing up to 30 metabolites. Low bioavailability after oral administration can be improved by micronization and then encapsulation of micronized progesterone suspended in oil in gel capsules.
The oral progestogens that are currently available to be used as adjuncts to estrogen for endometrial protection are micronized progesterone, dydrogesterone, medroxyprogesterone acetate (MPA), norethisterone or levonorgestrel.
The dose of micronized progesterone suggested in this context is 200 mg/day for 12–14 days each cycle in a sequential MHT regimen and 100 mg/day in continuous combined MHT regimens.
MPA can be given in a dose of 10 mg/day for 12–14 days in each cycle with sequential MHT or 5 mg/day in continuous combined MHT. Dydrogesterone preparations contain a dose of 10 mg/day for 12–14 days in each cycle with sequential MHT or 5 mg/day in continuous combined MHT.
Norethisterone can be given in a dose of 5 mg/day for 12–14 days in each cycle with sequential MHT or 1 mg/day in continuous combined MHT.
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