Estrogens

Types of estrogen

The primary estrogen in premenopausal women is 17-β-estradiol (E2), which is synthesized by developing ovarian follicles. Estradiol is oxidized to estrone (E1) and then to estriol (E3). Estrone is also produced in peripheral tissues by aromatization of androstenedione, an androgen precursor that is produced by both the ovaries and the adrenal glands; after the menopause, estrone produced in this way becomes the predominant estrogen. All of the estrogens are sulfated and glucuronidated before excretion.

Natural 17-β-estradiol undergoes first-pass metabolism when given by mouth, and other compounds have therefore been preferred for therapeutic purposes. For the estrogen component of the oral contraceptives, mestranol (ethinylestradiol-3-methyl ether) was originally used, but since it was suspected of adverse effects it was by 1969 largely replaced by unesterified ethinylestradiol. 17-α-estradiol has also been synthesized (or extracted from pomegranates) and studied, but it binds much more weakly than the 17-α congener to estrogen receptors. 17-β-estradiol in micronized form, to improve systemic availability, has also been used in various products, especially in Scandinavia.

For estrogen replacement therapy, the less potent estrogens, estrone and estriol, have been widely used, as well as the semi-synthetic compound epimestrol.

In North America, much publicity has for many years been devoted to the supposed merits of “equine estrogens,” also known as “conjugated estrogens” (Premarin), described as comprising a natural product extracted from the urine of pregnant mares. However, since pregnant mares were an inadequate source of starting material, these preparations have for a long time apparently been based primarily on synthetic substances (estrone with some equilin), although in some products a small amount of natural material may be present. The Food and Drug Administration in the USA long took the view that sodium estrone sulfate and sodium equilin sulfate were the sole active ingredients of the original product, but this was challenged by the manufacturers, who adduced evidence that dehydroestrone sulfate, and perhaps other components, could play a role. Overall, however, the view seems to be that the effects of Premarin are similar to those of other weak estrogens, whether given singly or in combination.

For injectable formulations used in estrogenic hormone replacement therapy, various esters of beta-estradiol have been most widely used.

Uses

Estrogens are used principally for:

• relief of the symptoms of the menopause;

• treatment of postmenopausal vaginal atrophy;

• contraception, in combination with a progestogen;

• hormone replacement therapy, alone or in combination with a progestogen, an androgen, or both.

Hormone replacement therapy should be distinguished from the short-term therapeutic use of estrogen (or hormonal combinations) around the time of the climacteric for the relief of acute (primarily vasomotor) symptoms; such treatment can generally be limited to some 6–12 months although if it is then withdrawn the symptoms may recur [ ]. Confusion between these two forms of treatment has led to a series of misunderstandings regarding the adverse effects of true hormone replacement therapy.

Oral contraception and hormone replacement therapy are dealt with specifically in separate monographs. Here the general adverse effects of estrogens for any indication are reviewed.

There is also interest in the possible neuroprotective effects of estrogens on the nervous system, since estrogen may act as an antiapoptotic agent, an antioxidant, or a neurotrophic modulating agent, promoting cross-talk with neurotrophic factors [ ]. This could in theory prove helpful in the treatment of conditions such as Parkinsonism, but no selective agent with such usefulness, and devoid of unwanted effects on other systems, has so far emerged. In the meantime, tibolone, sometimes described as a “gonadomimetic” agent, because of its ability to stimulate certain estrogen receptors selectively, has been used, although without any clear success, in the hope of potentiating the effects of fluoxetine on major depression [ ].

“Equine estrogens” (Premarin)

The controversy regarding the composition of Premarin and what are regarded as its generic equivalents has been outlined above. While still in use for hormone replacement therapy, these products have also been used as a means of reducing unwanted bleeding, for example in uremia [ , ], although their efficacy has been challenged. Estrogens have also been used in the treatment of bleeding in hereditary hemorrhagic telangiectasia [ , ].

General adverse effects and adverse reactions

Salt and water retention due to estrogens can cause weight gain and a rise in blood pressure. Changes in liver function tests can occur and jaundice is sometimes seen. Mild gastrointestinal upsets are not unusual. Unwanted endocrine effects include uncomfortable stimulation of the breasts and endometrial bleeding. In men, estrogens produce gynecomastia. Hypersensitivity reactions are rare and include urticaria, edema, and bronchospasm.

Estrogens can be associated with endometrial carcinoma, liver tumors, and breast tumors; they can also promote the further growth of pre-existing estrogen-dependent tumors.

When conjugated estrogens are used to control bleeding they are generally given only in short courses and are therefore well tolerated. As recommendations for control of bleeding involve administration of Premarin on a limited number of occasions (no more than five or seven doses) the usual hormonal problems associated with estrogens will be avoided. Gross hepatic disease is regarded as a contraindication. Headache, flushing, and nausea have been observed after intravenous injections and slow injection is therefore recommended.

Men taking estrogens generally do so in the course of palliative treatment for malignancies (prostatic carcinoma), for which high doses have sometimes been used. Estrogen therapy in men with prostate cancer may be superior to castration in terms of efficacy, but orally administered estrogens are associated with adverse effects: gynecomastia, loss of sexual function, and unacceptable cardiovascular toxicity [ ]. Low-dose estrogens in combination with anti-androgens or antithrombotic agents may be better tolerated.

Estrogenic effects of non-estrogens

Over the last 50 years, it has been realized that environmental chemicals, such as pesticides and industrial chemicals, can have hormone-like effects in wildlife and humans [ ]. These chemicals may:

• mimic the effect of endogenous hormones

• antagonize the effect of endogenous hormones

• alter the synthesis and metabolism of endogenous hormones

• alter the synthesis and metabolism of hormone receptors.

There have been reports that aviation crop dusters handling DDT had reduced sperm counts and workers at a plant producing the insecticide kepone had reduced libido, became impotent, and had low sperm counts. Subsequently, animal experiments showed that these pesticides have estrogen-like activity. Man-made compounds used in the manufacture of plastics interfered with experiments on natural estrogens. Some detergents and antioxidants are not themselves estrogenic, but on degradation during sewage treatment can release estrogenic alkyl phenols, such as bisphenol-A, nonylphenol, and phenylphenols. Polycarbonate flasks release bisphenol-A, which can also contaminate the contents of canned food in which polycarbonate coatings are used; bisphenol-A is also used in dental sealants and composites and can leach from teeth into saliva. Polystyrene tubes can release nonylphenol. The surfactant nonoxynol is used as intravaginal spermicide and condom lubricant; in animals it is metabolized to free nonylphenol. Other xeno-estrogens include the plasticizers benzylbutylphthalate and dibutylphthalate, the antioxidant butylhydroxyanisole, the rubber additive para-phenylphenol, and the disinfectant ortho-phenylphenol.

Comparative studies

The originally ambitious long-term international general practice trial of estrogens in the menopause (WISDOM), which had been intended to continue for 10 years [ ], was suspended after 12 months when the results of the Women’s Health Initiative cast doubt on the acceptability of this treatment. The abbreviated trial, as published in 2007, nevertheless accumulated data on 6498 woman-years, and has provided a helpful picture of adverse events in 2196 treated women compared with 2198 untreated controls. The number of women who took estrogens alone was almost the same as the number who took combined estrogen + progestogen treatment. Compared with placebo, the treated group had significantly more major cardiovascular events (7 versus 0) and episodes of venous thromboembolism (22 versus 3). However, there was no statistically significant difference in the numbers of breast or other cancers, cerebrovascular events, fractures, or overall deaths. The findings in those who took estrogens alone were very similar to those in women who took combined treatment. It should be borne in mind that these women were recruited for treatment at a relatively advanced age (50–69 years at randomization) and that the findings might be different from those in women in whom treatment was begun shortly after the menopause.

Various writers have advanced other reasons for regarding the findings of this study with a degree of caution. Ellen Grant has pointed out that of the women randomized to take part, 55% had already used HRT for a median of 5.3 years [ ]; in addition, many of the women must previously have used estrogens and progestogens for contraception. Women who had developed serious conditions or had died because of past hormone use would not be willing or available for randomization to take more HRT. What is more, many of the women must have entered the study in their early fifties and could not truly be regarded as late starters.

Cardiovascular

Estrogens have both wanted and unwanted effects on the cardiovascular system, depending on the manner in which they are used. Hormone replacement therapy is used in the hope of reducing the risk of ischemic heart disease after the menopause. The reduction in risk may be as much as 50% and is attributed variously to vasodilatation mediated by the endothelial production of prostaglandin I2 (prostacyclin), effects on coagulation factors and endothelial function, and improvements in serum lipids (increased concentrations of HDL cholesterol and reduced concentrations of LDL and total cholesterol) [ ], but variable effects on triglycerides. However, estrogens (especially as used in contraception but also postmenopausally) can have a marked effect on clotting factors and renin substrate, increasing the risk of thromboembolism.

The Coronary Drug Project in men taking different doses of estrogens showed a dose-related increase in myocardial infarction and thromboembolic diseases [ ].

A Greek group set out to determine in a randomized, double-blind study the effect of hormonal or antihormonal therapy on serum VE-cadherin in 28 healthy postmenopausal women, who received either 17-beta-estradiol (2 mg/day) with norethisterone acetate (1 mg/day) or alternatively raloxifene HCl alone (60 mg/day) for 6 months [ ]. Serum VE-cadherin, which was estimated at baseline and at month 6, fell significantly in both groups. These findings suggest that these drugs may preserve interendothelial junction integrity and control vascular permeability. Although this effect may favorably influence the progress of an atheromatous lesion, its clinical impact, for example on coronary artery disease, remains uncertain.

Respiratory

Allergic bronchospasm occurs very rarely with estrogens [ ], but has been reported several times in women with an existing allergic tendency or a history of asthma; some asthmatic women have worse symptoms during the luteal phase of the menstrual cycle. In affected cases, the link with estrogens can be demonstrated by rechallenge.

Nervous system

Various types of headache can occur; in patients with migraine, attacks can be precipitated, usually with prominent visual phenomena.

• In a woman with history of chorea in the distant past, a vaginal cream containing estrogens precipitated an attack.

In a randomized, double-blind, placebo-controlled arm of the Women’s Health Initiative, 10 739 postmenopausal women, aged 50–79 years, with prior hysterectomies, were randomly assigned to receive either conjugated equine estrogen 0.625 mg/day or placebo. There was an increased risk of stroke (RR = 1.39; 95% CI = 1.10, 1.77).

Estrogens can precipitate attacks of migraine [ ] and the problem has been reviewed, both as regards post-menopausal treatment [ ] and the use of estrogens in male-to-female transsexuals [ ]. The problem cannot be avoided in susceptible subjects, but it currently appears to be treatable in the same way as menstruation-related migraine, e.g. using sumatriptan 50–100 mg as required.

Sensory systems

Retinal vein occlusion [ ], retinal artery occlusion [ ], and optic neuritis [ , ] have been described in women taking estrogens. In older women, estrogens cause a slight rise in intraocular pressure [ ].

Psychological, psychiatric

The effects of estrogens on mood tend to be positive, and improved performance in intellectual tests has been described [ ]; this is in parallel with the known effects of endogenous estrogens. During the menopause some women become depressed and irritable, and the ability of estrogens to correct this has been delineated in various studies, including work with estradiol given transdermally [ ]. Some workers also claim increased vigilance, and have concluded that this is reflected in encephalographic changes. There is even some evidence of an improvement in mental balance and self-control when estrogens are given to demented and aggressive old people of both sexes [ ]. However, all of these effects of estrogens on mood or mental performance are only likely to last for as long as the treatment does, and the effects on mood may occur only at the start of treatment; altered mood can follow acute withdrawal.