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Pharmacology of hormones used in gynaecological treatment
Estrogens and Progestogens
Natural or synthetic estrogens are compounds that bind to estrogen receptors and exert biological effects characteristic of endogenous estradiol. Progestogens are synthetic versions of progesterone and bind to progesterone receptors, resulting in effects similar to endogenous progesterone.
Female sex hormones have a long history of therapeutic applications. In combination, estrogens and progestogens are used for contraception, menstrual regulation, treatment of endometriosis and postmenopausal hormone replacement therapy (HRT).
Exogenous estrogen used alone, unopposed by progestogen therapy, is of limited use because of its proliferative effects on the uterine endometrium, leading to irregular menstrual bleeding when used in premenopausal women and to endometrial hyperplasia when used alone as HRT.1 Thus, estrogen-only therapy in gynaecology is restricted to HRT use in women who have undergone hysterectomy. In contrast, progestogens used alone have widespread applications and are used in contraception, menstrual regulation in women suffering from dysfunctional uterine bleeding and menorrhagia and treatment of endometriosis and endometrial hyperplasia. Exogenous progesterone is used in assisted reproduction to provide support for embryo implantation in the luteal phase.
Endogenous Estrogens
In the reproductive years, the most potent endogenous estrogen is 17-beta-estradiol (E2), followed by estrone (E1). In young women, both are secreted by the ovaries, with a production rate of E2 ranging from 100–600 micrograms/day, varying during the menstrual cycle. Small amounts of E1 derive from aromatisation of androstenedione from the adrenal glands and ovaries. Estriol (E3) is the least potent physiological estrogen and is not a secretory product of the ovary. It is formed by irreversible metabolism of E1.
After the menopause, E1 is the predominant estrogen as ovarian secretion of all estrogens ceases. The residual production of E2 and E1 after the menopause originates from the peripheral aromatisation of circulating andro-stenedione and E2 and E1 are found in the range of 15 and 45 micrograms/day, respectively. As this aromatisation process occurs in adipose tissue, women who are obese may produce twice as much E2 and E1 as women who are not obese.
The estrogen receptor
Estrogens, through binding to their specific receptor in the target cell, promote development of secondary sexual characteristics in women and stimulate endometrial proliferation, thickening of the vaginal mucosa and maintenance of urogenital tissues. Estrogen receptors are present in many organ systems and demonstrate actions that are not directly related to reproduction, such as maintenance of bone strength, initiation and termination of the pubertal growth spurt and pigmentation of the nipples and genitals.
The estrogen receptor belongs to the steroid receptor superfamily, which comprises the glucocorticoids, vitamin D, thyroid hormone, androgen and retinoid receptors. Estrogen acts through two receptors, alpha and beta. The alpha estrogen receptor is found in endometrium, bone, breast cancer cells, ovarian stroma cells and in the hypothalamus. The expression of the beta estrogen receptor protein has been documented in kidney, brain, bone, heart, lungs, intestinal mucosa, prostate and endothelial cells. The presence of the receptor in a tissue does not predict its role in mediating estrogenic effects. For example, alpha receptors appear to be the chief mediator of estrogen’s actions on the skeleton. Osteoblasts express beta receptor but the actions of beta receptor agonists on bone are less clear. Some reports suggest that the effects of estrogen signalling through alpha and beta receptors are in opposition, while other studies suggest that activation of these receptors have similar effects on bone.
Different ligands may differ in their affinity for alpha and beta isoforms of the estrogen receptor. E2 appears to bind equally well to both receptors, whereas E1 and raloxifene bind preferentially to the alpha receptor and E3 and genistein bind preferentially to the beta receptor.
Estrogen metabolism
Circulating estrogens are metabolised primarily in the liver by conjugation and hydroxylation. Conjugation is catalysed by glucuronyl transferases and by sulphotransferases, whereas hydroxylation is catalysed by the enzymes of the cytochrome P450 complex. The residence time of E2 is prolonged by conversion to E1 and by enterohepatic recirculation of estrogen conjugates excreted in the bile. E2 is rapidly cleared from the circulation with a mean half-life of 1.7 hours. The half-life for E1 and E1 sulphate is about four times longer.
Effects of estrogen
The physiological effects of estrogens are influenced by sex hormone-binding globulin (SHBG) and albumin production. E2 bound to SHBG is not biologically active. Thyroxine and E2 itself promote SHBG production, while androgens, insulin, corticoids, progestogens and growth hormone suppress hepatic SHBG production.
Pharmacological estrogens
Orally administered natural estrogens are inactivated in the gut and the residual small amount that is absorbed undergoes considerable metabolism in the liver before reaching the circulation. In 1938, it was realised that the addition of an ethinyl group to E2 prevented inactivation and enabled efficient gut absorption. However, the first-pass hepatic effect was still present. Currently, most oral contraceptives contain ethinyl estradiol as the estrogenic component.
Natural estrogen preparations are derived from plant or animal sources and are widely used in HRT. They do not have potent enough effects on the E2 receptor to control the endometrium and menstrual cycle in premenopausal women and are therefore not used in the contraceptive pill. Conjugated equine estrogens contain the sodium salts of the sulphate ester forms of various naturally occurring estrogens derived from the urine of pregnant mares. Micronised estradiol is manufactured by the formation of extremely small particles of drug with a relatively high surface area to improve gastric absorption. E2 valerate, piperazine E1 sulphate and E2 cypionate are conjugated forms that have been modified for better absorption in the gastrointestinal system and are also used in HRT.
Selective estrogen receptor modulators
Selective estrogen receptor modulators are compounds that interact with estrogen receptors. Selective estrogen receptor modulators were originally thought to be anti-estrogens. However, it is now clear that they contain an admixture of agonist and antagonist activities.
The first selective estrogen receptor modulator, clomiphene citrate, a triphenylethylene, was synthesised in 1956 and is used widely in the treatment of polycystic disease and for ovulation induction. It acts centrally to block the negative feedback of estrogen and to induce a follicle-stimulating hormone surge of anterior pituitary gonadotrophs through positive feedback. In 1984, it was observed that clomiphene citrate attenuated bone loss in the oophorectomised rat, suggesting that it had estrogenic agonist activities on the bone. Clomiphene is a combination of two geometric isomers. The trans isomer, enclomiphene, is a partial estrogen whereas the cis isomer, zuclomiphene, is a pure estrogen.
Another triphenylethylene, tamoxifen, was subsequently shown to prevent bone loss in the oophorectomised rat. Tamoxifen acts as an estrogen antagonist in the breast but as an agonist in the skeleton and the cardiovascular system. Tamoxifen was not further developed as a bone-sparing agent as it causes endometrial stimulation and endometrial hyperplasia and adenocarcinoma in some women. Tamoxifen is widely used in the management of estrogen receptor positive breast cancer.
Raloxifene is a nonsteroidal benzothiophene that inhibits bone mineral density loss but does not stimulate the endometrium and is an estrogen antagonist for breast tissue. Raloxifene is not a steroid and hence not technically an estrogen but it possesses a phenolic ring – similar to the A ring of estradiol – necessary to obtain lodgement in the ligand-binding cavity of the estrogen receptor. There is no evidence that raloxifene decreases the incidence of nonvertebral fractures, so although raloxifene can be used for the prevention of vertebral fractures in women with osteopenia/osteoporosis, its use is probably not appropriate for women who are at high risk of nonvertebral fractures.
Endogenous Progesterone
Outside of pregnancy, progesterone is chiefly produced by the corpus luteum, with very small amounts produced by the adrenal cortex and the glial cells of the central nervous system. The production rate of progesterone in the preovulatory phase is less than 1 mg/day, which increases to 20–30 mg/day during the luteal phase. Progesterone is responsible for induction of secretory activity and decidual development in the endometrium in the estrogen-primed uterus. If pregnancy does not occur, withdrawal of progesterone results in menstrual sloughing of the endometrium. Progesterone is needed for the implantation of the fertilised ovum and maintenance of pregnancy. It increases viscosity of cervical mucus, promotes glandular development of the breast and increases basal body temperature. During pregnancy, the placenta eventually becomes the major source of progesterone and this placental progesterone is believed to inhibit uterine contractions, allowing for the maintenance of the gestation until the start of labour.
Effects of progestogens
Progestogens and progesterone, have a well-established anti-estrogenic effect on the endometrium. In an estrogen-primed endometrium, progestogens downregulate nuclear E2 receptors by inhibiting receptor synthesis and accelerating their turnover, and downregulate the genes required for epithelial growth, leading to reduced epidermal growth factor production. Progestogens promote differentiation of glands and stroma, decidualisation and secretory activity of the endometrium, increase blood vessel volume and stimulate secretion of insulin-like growth factor binding protein-1. Progestogens also stimulate 17-hydroxysteroid dehydrogenase production, which converts E2 to the weaker estrogen, E1 sulphate, and induce endometrial sloughing and uterine bleeding.
Progesterone and progestogen metabolism
Progesterone and progestogens are metabolised primarily by the liver, largely to pregnanetriols and pregnanediols, which are then conjugated in the liver to glucoronides and sulphates. These metabolites are excreted in the bile and may be deconjugated and further metabolised in the gut. There is no significant enterohepatic circulation of progesterone.
Pharmacological properties of progesterone and progestogens
When first produced pharmaceutically, progesterone was ineffective when given orally, as it is metabolised extensively in the gastrointestinal tract by microorganisms and digestive enzymes. Although micronised progesterone results in more efficient absorption from the gastrointestinal tract, large doses need to be given often to obtain therapeutic serum levels. However, natural progesterone is also available in transvaginal or transrectal suppositories and absorption is sufficient for it to be used as the progestogenic component of HRT regimens.
Progestogens are synthetic preparations with progesterone action that were developed to be orally effective. These are divided into the 21-carbon steroids derived from 17-alpha-hydroxyprogesterone and the 19-carbon steroids derived from nortestosterone.
The 21-carbon steroids (for example, medroxyprogesterone acetate and dydrogesterone) simulate the profile of progesterone more closely, especially in their effects on the hypothalamic–pituitary system and on carbohydrate and lipid metabolism. Medroxyprogesterone acetate is probably the most widely used compound in this group. It is used in depot preparations for contraception and in oral form for postmenopausal hormone replacement and treatment of endometriosis and menorrhagia.
Progestogens derived from 19-nortestosterone are subdivided into compounds related to norethisterone (estranes) or to levonorgestrel (gonanes). Norethisterone is widely used in oral contraceptives and has androgenic properties and potent progestational activity. Many related progestogens have since been developed, including norethisterone acetate and etynodiol diacetate. However, all are converted in vivo to norethisterone before they are active. The gonanes are all derived from norgestrol, made from the addition of a methyl group to norethisterone. Norgestimate is a prodrug, which is metabolised in two steps to the active levonorgestrel. Gestodene and desogestrel are closely related gonanes developed for use in the contraceptive pill and in HRT. An active intermediate metabolite of this conversion, levonorgestrel oxime, is a component of the weekly contraceptive patch. Drospirenone, a new progestogen for oral contraception, is chemically related to spironolactone and demonstrates potent progestational activity, together with antimineral corticoid and antiandrogenic properties.
Routes of administration of progestogens
A progestogen-containing intrauterine device (the intrauterine system containing levonorgestrel), subcutaneous pellets, transdermal cream, transdermal patch, vaginal suppositories and intramuscular injection of progesterone are all delivery systems in use, although oral administration remains the most common mode of delivery. For HRT, progestogens are added in either a cyclic or continuous fashion to prevent endometrial hyperplasia and endometrial cancer. This is usually accomplished using the oral route, the transdermal patch or the progestogen-containing intrauterine system.
Adverse effects of progestogens
Common symptoms of progestogens include weight gain, acne, fluid retention, headaches and breast tenderness. Sedation and mood changes reflect progestogenic effects on the central nervous system and may be related to progestogen binding to a membrane receptor of gamma aminobutyric acid in the central nervous system, which is the same receptor site for benzodiazepines and barbiturates.
Many progestogens (particularly 19-carbon compounds) when used alone cause androgenic effects such as acne and hirsutism owing to their similarity to testosterone. However, when combined with ethinyl estradiol in oral contraceptives, the suppression of ovarian androgens and the beneficial effect on SHBG induces an overall antiandrogenic effect in most women. Drospirenone, given its similarity to spironolactone, may be associated with less bloating and weight gain.
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