8th Postgraduate Course for Training in Reproductive Medicine and Reproductive Biology
Hormone Replacement Therapy (HRT)
D. de Ziegler
Department of Obstetrics and Gynecology, Nyon Hospital
Department of Obstetrics and Gynecology, Geneva University Hospital
Introduction
Menopause is a genetically programmed arrest of the ovarian function. It results in endocrine deficiencies that affect all women by the age of 50. While menopause is natural, the extent of life expectancy beyond it has markedly increased as a result of progresses in medicine and hygiene. At the turn of the 20th century, an American woman reaching the age of 50 could reasonably expect to live 9 more years. This has more than tripled today with mean life expectancies in excess of 80 years in most countries. The increase in life time spent beyond menopause has brought new expectations for women (professional and personal ones) together with its toll of negative consequences (increase in osteoporosis and its complications, CHD and Alzheimer's disease).
The basic aim of hormonal replacement therapy (HRT) is to substitute ovarian hormones in order to avoid the unwanted symptoms of menopause (HF, psychological symptoms) and its dreadful consequences (increase in bone loss and risk of osteoporosis and increase in CHD). On a more subtle register, the objective of HRT is also to maintain the individual`s energy level and sensation of well being so that it remains in tune with the increased personal expectations voiced by 50 year old women today. While pursuing these goals, HRT must also be safe and practical as well as able to satisfy individual differences and preferences for hormone delivery systems and/or options.
Estrogen therapy
One of the 2 hormones produced by the ovary is estradiol (E2), the most active natural estrogen found in humans. Daily production rates of E2 fluctuate between a nadir of approximately 0.03 mg/24h during the early follicular phase to a maximum of 0.4 - 0.6 mg/24h. just prior to ovulation. Mean daily production rate during the menstrual cycle is of approximately 0.2 mg/24h. The preovulatory increase in E2 is believed to only be important for ovulation. In HRT regimens, E2 or other estrogens have been administered at doses set to achieve the estrogen treatments primary objective, namely, protecting bone in order to avoid osteoporosis. Hence, for each estrogen preparation available, the minimal effective dose on bone has been determined. These are the most commonly used doses in HRT regimens. They are approximately equivalent to the amount of E2 produced in the early follicular phase of the menstrual cycle (0.03 mg/24h) but are markedly inferior (approximately 1/3) to the estrogen doses contained in low dose oral contraceptives or the mean production route during the menstrual cycle. Comparative bone sparing doses of estrogens are given in Table 1.
| Estrogen preparation | Route of administration | Bone sparing or commonly used dose |
| Conjugated Equine Estrogen (Premarin) |
oral | 0.625 mg/24h |
| Micronized E2 (Estrace and others) |
oral | 1 - 2 mg/24h |
| E2 valerate (Progynova) |
oral | 2 mg/24h |
| Ethinyl-E2 (Estinyl and others) (also constituant of most oral contraceptives) |
oral | 0.01 mg/24h |
| Transdermal E2 "patches" (Estraderm and other newer products) |
transdermal | 0.05 mg/24h 3.5 day or 7 day "patches" |
| Percutaneous E2 gel Oestrogel and other newer gels) |
transdermal | 1.5 g of gel containing approximately 0.05 mg of E2 |
Effects of estrogens on lipids and cardiovascular diseases
Estrogens particularly when administered orally have been documented to increase cholesterol-HDL and lower cholesterol-LDL levels. Because of the known benefits of these changes on cardiovascular risk, it has been postulated that the impact of estrogens on lipids was the primary mechanism by which ovarian hormones protected against CHD. Today, we know that the impact of estrogens on blood lipids and notably HDL and LDL albeit important is not the primary cardioprotective mechanism. Rather, more emphasis has been placed on direct vascular effects of estrogens. Interestingly, while lipid effects are amplified mainly by oral administration, direct vascular effects are blood level dependent and therefore independent of the route of administration selected.
Effects of estrogens on HF and other menopausal symptoms
Estrogen treatments are highly effective for correcting HF in menopausal women. This effect is blood level dependent and route of administration independent. In women suffering from an unusual high incidence of HF (> 10 HFs/day), raising E2 to early follicular phase levels remained insufficient to completely alleviate HF in over half of them. Hence, in some individuals, doses of estrogen higher than minimal bone sparing doses are necessary to correct menopausal symptoms or adjunct effects of progesterone/progestins are necessary. Characteristically however, sleep disorders are easily corrected by estrogen treatment. Younger women and particularly women suffering from premature menopause require higher estrogen doses to match their level of activity.
Progestogens
It has been amply documented that estrogens administered alone to women whose uterus is present increases the risk of endometrial hyperplasia and/or cancer. This results from an unopposed stimulation of endometrial growth. Normally, in the menstrual cycle, the growth promoting properties of E2 are antagonized by the cyclical production of progesterone after ovulation. Progesterone opposes the growth promoting effects of E2 by at least 2 mechanisms: 1) progesterone lowers the E2 receptors (E2R) content of endometrial glands, and 2) enhances the transformation of E2 in the endometrial tissue into the less active estrogen, E1. In premenopausal women, endometrial hyperplasia is only seen in women who suffer from chronic anovulation and therefore are not exposed to progesterone. Conversely, endometrial hyperplasia and/or cancer is never seen in women who ovulate regularly.
There is now a large body of evidence indicating that the addition of a gestagenic substance to estrogen therapy completely reverses the risk of hyperplasia seen with estrogen-only treatments. In the micronized form, progesterone is absorbed orally but its bioavailability is catastrophic because more than 90% of the amount of progesterone absorbed is metabolized during the first liver pass. This leaves down stream from the liver, in the general circulation very high levels of progesterone metabolites, notably 5a reduced ones and very little progesterone. Progesterone metabolites are responsible for the psychological side effects including the drowsiness which is notoriously induced by oral progesterone.
To circumvent the high degree of liver metabolism of progesterone synthetic progestins have been conceived. These are man made molecules designed to retain the original properties of progesterone on the endometrium while resisting enzymatic degradation and remaining active orally. The lead products are medroxyprogesterone acetate (MPA) and norethisterone acetate (NETA). Both these molecules have proven efficacy on the endometrium (prevent the risk of hyperplasia) but exert various side effects including psychological ones that are molecule specific, route independent and not seen with native progesterone.
In the case of MPA, it has been documented this synthetic molecule does not share the non-genomic properties of progesterone that are mediated through an activation of the GABAA receptor complex. In many patients side effects brought by synthetic progestins must be recognized as they are, responsible for the notoriously poor long term compliance that characterizes HRT. as stated earlier, MPA also antagonizes the beneficial effects of estrogen therapy on the cardiovascular system.
Recently, new synthetic progestogens have been developed particularly in Europe. These products have been less intensively tested than MPA and NETA and some of their effects remain imperfectly known. It has been claimed however, that they may be more cardiovascular friendly but a view still challenged by some.
Route of administration
Estrogens and synthetic progestins can be administered orally. Because of hepatic metabolism, the daily dose of E2 must be approximately 10-20 times higher than ovarian production of E2 to be matched. E1 levels however, are markedly higher (10x) than those of E2. This reflects the intense GI tract metabolism but appears to be of no known clinical consequence. The amounts of E2 reaching the liver are however supraphysiological which increases some liver proteins that are estrogen sensitive. This includes some coagulation factors which elevation may result in a slight and dose dependent increase in blood coagulability. Non-oral administration of E2 such as achieved through transdermal patches avoids these consequences. Synthetic estrogens such as ethinyl-E2 (EE) affect liver proteins irrespective of the route of administration as in this case the effect is molecule dependent. Natural progesterone is very poorly effective when administered orally, and the high levels of 5a reduced metabolites produced induce significant drowsiness. Progesterone can not be administered transdermally because of poor skin permeability. Hence, the only practical non-oral route is vaginal. Recent data have indicated that vaginal administration results in unexpectedly high uterine levels which reflect some degree of direct vagina to uterus transport or "first uterine pass effect". Hence, vaginal administration of progesterone is highly effective and creates very little side effects. Synthetic progestins such as MPA and NETA are best administered orally. Their efficacy on the endometrium has been amply documented. Furthermore, their unwanted effects on liver proteins (e.g. increase in cholesterol-LDL) and their psychological side effects are molecule dependent and route independent. Hence, while transdermal systems delivering NETA exist, there is no good rationale nor practical advantage at administering these hormones non-orally.
Hormone treatment in hysterectomized women
In hysterectomized women only estrogen replacement is strictly necessary. Indeed, there is no imperious need for administrating progesterone/synthetic progestins other than for preventing the risk of endometrial hyperplasia and/or cancer. Characteristically, hysterectomized women show better and longer compliance to treatment than intact women. This should be taken as a strong indicator that it is the side effects generated by progestins which together with bleeding hamper long term HRT compliance.
Hormone treatment in high risk individuals
More and more often, we are confronted with the need to prescribe HRT to women who suffer from various chronic medical impairments. In these individuals, the high risk characteristics of their condition should impose greatest caution. First and before all, we must be certain that any prescribed treatment will not worsen the affecting ailment. In these vulnerable individuals, the exact effects of synthetic hormone molecules on deteriorated organ functions may remain enigmatic and speculative (and potentially worrysome). Hence, it is important to remember that it is always possible to offer physiological replacement to these patients with non-oral administration of the native ovarian hormones, E2 and progesterone. E2 can be administered from transdermal patches or gels while progesterone has to be taken vaginally 10 days/month.
Conclusion
HRT aims at treating the symptoms of menopause and preventing its consequences on bone mass and cardiovascular risk. It should be tapered to the patients` individual needs. Multiple options are available today, ranging from simple oral regimens to natural non-oral treatments featuring transddermal E1 and vaginal progesterone.