The Emerging Role of Estrogen in Women’s Health

Introduction

Estrogen is probably the most widely known and discussed of all hormones. Contrary to popular belief, estrogen is not an exclusively female hormone, but is produced by both men and women. However, its role in men is not entirely clear.¹

Estrogen is an essential part of a woman’s reproductive processes. It performs the following tasks in women:²

• Contributes to the development of secondary sex characteristics at the time of puberty
• Promotes cell growth, including signaling the growth of the blood-rich tissue of the uterus during the first part of the menstrual cycle
• Prepares the uterus for pregnancy by enriching and thickening the endometrium
• Stimulates the maturation of the egg-containing follicle in the ovary
• Softens the cervix and produces the right quality of vaginal secretion to allow the sperm to swim
• Lubricates the passage during intercourse
• Acts as a mood elevator and gives a feeling of well-being
• At menopause, the estrogen level goes down, leading to hot flashes, sleep disturbances, mood swings, vaginal dryness, etc.
• Lowers LDL, increases HDL, decreases lipoprotein(a) and homocysteine
• Affects every neurotransmitter in the brain, including serotonin, dopamine, GABA
• Adds moisture to skin
• Affects brain function responsible for memory and motivation and regulation of fine motor skills

Estrogen is produced in the ovaries, adrenal glands and fat tissues. More specifically, the estradiol and estrone forms are produced primarily in the ovaries in premenopausal women, while estriol is produced by the placenta during pregnancy.¹

Types of estrogen

Steroidal

Estrogen in our body actually is not a single hormone but a trio of hormones working together. These are natural steroid hormones produced within the body. All these forms of estrogen are synthesized from androgens, specifically testosterone and androstenedione, by the enzyme aromatase.³   The three components of estrogen are estrone (E₁), which is the predominant circulating estrogen during menopause; estradiol, which is the predominant estrogen during reproductive years; and estriol (E₃), which is the predominant circulating estrogen during pregnancy.³

Non-steroidal

Certain synthetic and natural non-steroidal substances also possess estrogenic activity. They are xenoestrogens (synthetic substances), phytoestrogens (plant products) and mycoestrogens (produced by fungi).⁴

Role of estradiol in female fertility

Estradiol valerate is a natural, bio-identical form of estrogen, and plays a crucial role in the normal growth and development of the female reproductive organs, as well as the maturation of the egg in the ovary. It is responsible for initiating the surge in follicle-stimulating hormone (FSH) and luteinizing hormone (LH) that induces ovulation. Together with progesterone, estradiol prepares the endometrial lining of the uterus for successful implantation of the fertilized zygote.⁵

Benefits of micronization

Estradiol valerate is now available in micronized form. Micronization imparts the following benefits:

• Better dissolution
• Better absorption (Fig. 1)
• Markedly increased bioavailability
• Desired clinical efficacy

Estradiol in Assisted Reproductive Technologies (ART)

Assisted Reproductive Technologies (ART), such as in vitro fertilization and embryo transfer, are resorted to when conventional infertility treatments fail. In some types of ART, fertilization occurs outside the uterus, and the formed embryo is then implanted into the uterus. For a successful implantation to occur, the endometrial lining of the uterus must be properly primed to receive the embryo. An endometrial thickness of 9-14 mm is associated with higher implantation and pregnancy rates as compared to an endometrial thickening of < 7 mm (Fig. 2).

This can be achieved by administering estradiol and progesterone prior to implantation during the normal menstrual cycle. Estradiol causes the endometrial cells and glands to proliferate during the first half of the cycle, while progesterone stimulates increased secretion from glands during the second half. Priming the endometrium increases the chances of the embryo attaching successfully.⁵

A challenge of in vitro maturation (IVM) treatment in some women is insufficient development of the endometrium prior to embryo transfer. In a study by Elizur et al,⁶   women with endometrial thickness <6 mm on days 6-10 ultrasound scan of IVM treatment were given micronized 17beta-estradiol. As a result, the endometrial thickness was significantly improved, being 8.72 ± 0.85 mm on the day of embryo transfer (ET), and implantation rate (IR) of 15.42% against 9.6% after the day of oocyte retrieval.

Another study⁷   tried to find out if estrogen used since the beginning of the menstrual flow could improve endometrial tissue compared to standard endometrial preparation for in vitro maturation cycles. For this, 20 women with polycystic ovary syndrome were assigned to two estrogen therapy schedules:

• Standard schedule – estrogen began on the day of planned egg retrieval (dosage was based on endometrial thickness)
• Long schedule – estrogen began on the first day of menstruation

In this study, one week after the day of planned egg retrieval (probably 1 or 2 days after embryo transfer) only 15% (3 patients) of the women on the standard schedule achieved 8 mm of endometrial thickness and 2.5 mL of endometrial volume, as opposed to 100% (20 patients) in the long schedule.

The endometrial thickness and volume both on the day of planned egg retrieval (DPER) and one week later (OWL) are shown in Fig. 3.

Thus, early use of estrogen was found to improve endometrial tissue and also required lower daily dosage.

Jung and Roh⁸   conducted a study to see if pregnancy rates for hMG (human menopausal gonadotropin)-stimulated IVF-ET (in vitro fertilization-embryo transfer) can be increased by estradiol (E₂) supplementation from the early proliferative phase to the late secretory phase of the endometrium. They recruited 81 infertile women with pure tubal factor, who were randomized into two groups as follows:

• Control group: No E₂ supplementation
• Study group: Oral E₂ supplementation (2 mg twice a day) from the early proliferative phase starting on the third day of the menstrual cycle to the late secretory phase of the endometrium, with hMG stimulation for ovulation induction starting on the sixth day of the menstrual cycle

Compared with the control group (n = 27 cycles), the E₂ supplementation group (n = 58 cycles) had a significantly higher pregnancy and implantation rates per ET. However, there was no statistically significant difference in the fertility rates per retrieved oocytes between the two groups (Table 1).

These results suggest that E₂ supplementation from the early proliferative phase to the late secretory phase of the endometrium in hMG-stimulated IVF-ET increases the receptivity of the endometrium for transferred embryos and clinical pregnancy rates.

A prospective, randomized study⁹   was conducted to evaluate the effect of adding E₂ to progestin supplementation during the luteal phase on pregnancy and implantation rates in patients undergoing IVF cycles. Patients who were undergoing IVF with controlled ovarian hyperstimulation using a GnRH analog and who had E₂ 2,500 pg/dL at the time of hCG administration were selected for the study. Significantly higher E₂ levels were found during the luteal phase in the group that received E₂ supplementation, and significantly higher pregnancy and implantation rates were recorded in the patients who received E₂ supplementation and were treated with the long GnRH analog protocol. Hence, the addition of E₂ to the progestin support regimen may have a beneficial effect on pregnancy and implantation rates in patients who are treated with the long GnRH analog protocol for controlled ovarian hyperstimulation and for whom luteal support with hCG is contraindicated.

As adjunct to clomiphene

Administration of clomiphene citrate (cc) is the first step in the induction of ovulation. However, this drug is known to possess antiestrogenic properties, which reduces the pregnancy rate. Hence, estradiol valerate is used as an adjunct to counter these effects. The effect of addition of estradiol to CC on endometrial morphology and pinopodes was investigated by Favaedi et al¹⁰   in a randomized clinical trial. The study population was 30 infertile women who were clomiphene-resistant in the previous cycles. These women were divided in the following 3 groups:

• Group 1: Clomiphene 150 mg/day, administered from day 5 to 9 day of cycle
• Group 2: Clomiphene plus estradiol valerate
• Group 3: Clomiphene plus progesterone

There were no significant differences in endometrial thickness on day 14 among the three groups of ovulation induction. Endometrial thickness was 7.55 ± 1.74, 7.87 ± 1.39 and 8.00 ± 1.85 mm on the day 14 of cycles. Pinopodes were 27.72 ± 21.8, 39.4 ± 28.9 and 27.69 ± 19.05, respectively. There were no meaningful differences between groups for pinopodes between three groups but the difference was significant when the clomiphene + estrogen group was compared with the other groups.

These results showed that adding estradiol valerate to clomiphene can positively affect endometrial morphology and increases the pinopodes on implantation window during induction of ovulation.

Effects of estrogen therapy in postmenopausal women

Hormonal therapy is often prescribed to relieve the symptoms of menopause. This can involve the use of either estrogen alone or with progesterone, or progestin. Progestin is added to estrogen to prevent endometrial hyperplasia, which can lead to uterine cancer. Patients with an intact uterus are given estrogen plus progesterone or a progestin, while those who have undergone a hysterectomy receive only estrogen.¹¹

Benefits of estrogen replacement therapy (ERT) far outweigh the potential risks. In a recent randomized trial of 1006 women, Schierbeck et al¹²   found a significantly decreased risk of the composite endpoint of death, heart failure, or myocardial infarction when hormone replacement therapy was started early in postmenopause. The beneficial effect occurred in the 10 years randomization phase and was maintained for an additional six years of non-randomized follow-up. This finding was not associated with an increased risk of cancer (including breast cancer), stroke, deep vein thrombosis, or pulmonary embolism. These data imply that hormone therapy started in recently menopausal women and continued for a prolonged duration does not increase or provoke adverse cardiovascular events, such as mortality, stroke, heart failure or myocardial infarction.

Effects on symptoms of surgical menopause

The sudden and abrupt decrease of sex steroids secondary to oophorectomy, radiation or chemotherapy can lead to the premature onset of rapid and severe climacteric symptoms, including hot flashes. Estrogen replacement therapy (ERT) provides relief from these symptoms and thus improves the quality of life.¹³

This was demonstrated in a study¹⁴   in which oophorectomized women who received either estrogen, androgen, or a combined estrogen-androgen preparation attained lower depression scores compared to a placebo group. Withdrawal of steroids resulted in higher depression scores in all oophorectomized women compared to those of a hysterectomized control group with intact ovaries.

Effects on abdominal obesity

The hormonal changes across the perimenopause substantially contribute to increased abdominal obesity which leads to additional physical and psychological morbidity. Compared to premenopausal women, postmenopausal women have been found to have a significantly larger visceral fat area.¹⁵

Obesity is associated with dysmetabolism and endangers the healthy equilibrium of sexual hormone production and regular menstrual cycles in women, which are the prerequisites not only for reproductive capacity but also for somatic health.¹⁶   There is strong evidence that estrogen therapy may partly prevent this menopause-related change in body composition and the associated metabolic sequelae.¹⁷

Effects on cardiovascular health

Evidence from epidemiological studies indicates that estrogen replacement therapy in postmenopausal women can reduce the risk of coronary heart disease. Current users particularly appear to enjoy the most substantial cardiovascular benefits. In addition, both animal and human studies show that estrogen use lowers low-density lipoprotein cholesterol (LDL-c) levels, increases high-density lipoprotein cholesterol (HDL-c) levels, improves blood flow, and reduces atherosclerosis.¹⁸

In order to determine the effect of postmenopausal estrogen therapy on the risk of cardiovascular disease, 48,470 postmenopausal women, who were participants in the Nurses’ Health Study, were followed up for 10 years. It was found that current estrogen use was associated with a reduction in the incidence of coronary heart disease as well as in mortality from cardiovascular disease.¹⁹

A prospective, observational cohort study²⁰   of 70,533 postmenopausal women found a lower risk of major coronary events among current users of hormone therapy, compared with never-users.

In another study,²¹   the relation between cardiovascular disease and postmenopausal hormone therapy was examined in 59,337 women from the Nurses’ Health Study, who were followed up for 16 years. It was observed that women who took estrogen with progestin or estrogen alone experienced a marked decrease in the risk of major coronary heart disease as compared with women who did not use hormones.

One of the causes of atherosclerosis is oxidative stress. A study by Castanho et al²²   observed that hormonal therapy (HT) in postmenopausal women produces beneficial antioxidant and anti-atherosclerotic effects by ameliorating the plasma lipid and lipoprotein profiles, increasing plasma catalase activity and attenuating the association between cardiovascular risk factors and early atherosclerosis.

Effects on brain health

Observational studies suggest reduced risk of Alzheimer disease (AD) in users of HT. Shao et al²³   found that the risk of AD was reduced by 30% in women who used any type of HT within 5 years ofmenopause.

Effects on breast cancer

In obese elderly women who have never used hormone replacement therapy (HRT), breast cancer risk is high due to their continuousestrogenloss and increasing insulin-resistance. By contrast, obese postmenopausal women using HRT have a decreased risk of breast cancer as the protective effect ofestrogen substitution may counteract their obesity-associated systemic alterations.¹⁶

Since postmenopausal women with breast cancer suffer from hormonal disturbances which can be implicated in the pathogenesis of the cancer, it might be helpful to delay the onset of cancer by normalizing the levels of these hormones. This can be satisfactorily done by appropriate hormonal therapy.²⁴

Effects on bone health

It is well known that polyarticular osteoarthritis (OA) is more common in females, particularly after menopause. This suggests a possible involvement of female sex hormones in the maintenance of cartilage homeostasis. Several animal models have demonstrated structural benefits of estrogens, as well as significant effects on joint inflammation. This is in line with clinical data using biochemical markers of joint degradation which demonstrated approximately 50% inhibition of cartilage destruction. These finding were recently validated in the Women’s Health Initiative (WHI), where women takingestrogenshad significantly less joint replacement. In fact, the pleiotropic effect ofestrogenson several different tissues may match the complicated etiology of OA in some important aspects.²⁵

Prestwood and colleagues²⁶   studied the effects of three doses of micronized 17beta-estradiol on bone turnover, sex hormone levels, and side effects compared with placebo in healthy older women. They noted that low dose of estrogen (0.25 mg/day 17beta-estradiol) reduced bone turnover to a similar degree as that seen with usual replacement therapy (1.0 mg/day 17beta-estradiol), but had a side effect profile similar to that of placebo. Thus, 17beta-estradiol in the dose of 0.25 mg/day may be an effective and tolerable agent for the treatment of osteoporosis in older women.

Effects on skin health

Skin is an estrogen responsive organ, containing estrogenreceptors, which decline in number as menopause sets in. Several studies have demonstrated the antiaging properties of estrogen replacement therapies in postmenopausal women.²⁷

Deficiency of estradiol (E₂) renders the skin more susceptible to oxidative damage, as evidenced by the accelerated decline in skin appearance in the perimenopausal years. A study²⁸   conducted to further elucidate the effects of estrogens on skin at the cellular level found that the menopause-associated estrogen decline is involved in reduced collagen production and that E2 can counteract the detrimental effects of oxidative stress on the dermal compartment during skin aging.

Conclusion

Estrogen is an essential part of the female reproductive processes, and is involved in almost all aspects of a woman’s health. Estrogen replacement therapy has been found to ameliorate menopausal symptoms and exert beneficial effects on almost all systems of the body

Estradiol valerate is a natural, bio-identical form of estrogen, which is now available in micronized form, and hence can be better absorbed. It plays important roles in female health, including fertility, ART, obesity, cardiovascular health, brain health, skin health and bone health. It has been found to be superior to other estrogens like ethinyl estradiol and conjugated estrogens.

References

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