Choosing the right estrogen in hormone replacement therapy and infertility

Post-menopausal hormone replacement therapy

Perimenopause and menopause: An overview

Menopause is the permanent cessation of menstruation that marks the end of the natural reproductive lifespan of a woman.^1,2     Menopause is characterized by an array of changes in the female body that are a result of deranged reproductive hormonal dynamics. A transitional period marked by accelerated loss of ovarian follicles, called the menopausal transition or perimenopause, is invariably seen prior to menopause. The period commences with the onset of menstrual irregularity (mean age of onset-47.5 years) and can span over several years.^3,4     Perimenopause heralds diverse endocrinal changes that lead to near complete cessation of ovarian hormone secretion and menstruation. Amenorrhea for 12 months, secondary to loss of ovarian activity marks the onset of the post-menopausal period. The natural traverse of menopause and post-menopause is typified by several biological and behavioral changes including skeletal derangements, declining sexual and cognitive functions, sleep disturbances and vasomotor symptoms.⁴

Insights into the menopausal endocrine milieu

Reproductive ageing has remarkable effects on the hormonal integration of women.⁵   A fall in the number of ovarian follicles to a critically low level is believed to be the chief contributory factor in the onset of the menopausal transition. Besides, notable changes in the neuroendocrine axis arising from the loss of ovarian function also become apparent at about the age of 40. Dramatic swings in estradiol and gonadotropin levels are characteristic of menopausal transition. Progressive decline in inhibin A and B (peptide hormones), concomitant with a selective rise in follicle-stimulating hormone (FSH) constitute important markers of ovarian ageing; they initially maintain folliculogenesis and estradiol secretion. Subsequently, progesterone, luteinizing hormone (LH) and gonadotropin-releasing hormone pulse frequency decrease significantly. Within 1-2 years after onset of menopause, FSH levels are markedly elevated, luteinizing hormone (LH) and testosterone levels moderately so, while estradiol and inhibins are either low or absent.^5-7

Robust clinical research in the past years has revealed much to support the above-mentioned endocrinal variations in menopausal women. A prospective longitudinal study undertaken by Burger and coauthors⁸   evaluated the levels of estradiol in women traversing the menopausal stages. The results showed that estradiol concentrations decreased from 306 pmol/l in the pre-menopausal subjects to 89 pmol/l and 41 pmol/l in peri- and post-menopausal subjects, respectively (figure 1). These findings were corroborated by another study that demonstrated progressively falling concentrations of estradiol in perimenopausal women approaching the final menstrual period.⁹   In contrast, testosterone levels have been shown to rise with increasing age in menopausal women. Ala-Fossi et al¹⁰   investigated the pattern of ovarian testosterone secretion during the last few years of reproductive life and after menopause. A noteworthy positive correlation was found between age and ovarian testosterone levels. In pre-menopausal state, it was 1.5 nmol/l, in perimenopausal state 2.2 nmol/l, and 2.5 nmol/l in post-menopausal state, respectively (figure 2). In face of the notable decreases in estradiol concentrations and relative androgen excess, a rise in the testosterone to estradiol ratio is inevitable. A prospective cohort study¹¹   demonstrated that the total testosterone to estradiol ratio increased by 10.1% per year during 5 years of follow-up of pre-menopausal and perimenopausal subjects.

The aforementioned hormonal fluctuations during the natural traverse of menopause may have serious health implications. Ample data exists to cast light on the health outcomes associated with menopause transition.

Health implications: Focus on declining estradiol

Loss of ovarian function resulting in deficient circulating estradiol accounts for a notable decline in estrogen dependent endocrine and behavioral responses. Falling estrogen levels are believed to adversely affect the hippocampus circuits leading to impaired cognition and decreased metabolic activity. Concurrently, neuroendocrine response diminishes with advancing age which further contributes to declining reproductive function.¹²   All these processes together result in a variety of undesirable health effects that become manifest during perimenopause and may last years after menopause transition.¹³

Common self-reported negative symptoms include vasomotor symptoms (hot flushes and night sweats), vaginal symptoms, urinary incontinence, disturbed sleeping/insomnia, decreased libido, depression/anxiety, memory loss, joint pains, breast tenderness and weight gain. However, both basic and clinical research has revealed much to suggest that the only symptoms that are specifically related to hormonal changes of menopausal transition are vasomotor symptoms, vaginal symptoms, troubled sleeping and breast tenderness.¹⁴   In face of the inconsistent findings obtained from population-based studies, the prevalence and severity of these symptoms remains variable. A retrospective study¹⁵   was conducted to evaluate the prevalence of menopausal symptoms among Iranian women. The results unveiled that the most prevalent symptoms were irritability (72.1%) and joint pain (70.6%) followed by depression (59.7%). A Nigerian study,¹⁶   on the other hand, showed that joint discomfort was the most commonly reported symptom among midlife women (59.0%), followed by physical and mental exhaustion (43.0%), sexual problems (40.4%), and hot flushes (39.0%).

In addition to the above-mentioned, low serum estradiol may have perceptible effects on important systems of the body such as the skeletal and cardiovascular systems.^17,18

Skeletal effects

Among various skeletal morbidities, osteoporosis is reportedly the most prevalent. Estrogen deficiency increases bone remodeling, disrupting the balance between bone formation and resorption. This increase in bone remodeling persists for several years and is accountable for accelerated of bone loss. These effects heighten the risk of pathological fracture and increase morbidity and mortality among menopausal women.¹⁸     A cross-sectional study¹⁹   conducted on post-menopausal women aged 45 years and above showed an age-dependent increase in the prevalence of osteoporosis. The prevalence was 30.6% in women 45-64 years old, 52.5% in women aged 65-74, and 68.7% in the women aged 75 years or above (figure 3). Catalano and coworkers²⁰   demonstrated a similar trend for the risk of osteoporotic fractures in a cohort of post-menopausal women. The median risk of major osteoporotic fractures was 4.9 % in women younger than 55 years, 7.3% in 55-65 year-old and 17.5% in those older than 65 years (figure 4).

Cardiovascular effects

The inexorable age-induced changes and estrogen deficiency together amplify cardiovascular risk in the post-menopausal state.¹⁷   Cardioprotective actions of endogenous estrogen are well-documented in literature. A wealth of data suggests that it favorably alters plasma lipid profiles, exerts antioxidant effects and positively modulates vascular response to vasoactive agents.²¹   Hence, post-menopausal decline in estrogens may detrimentally affect cardiometabolic functions.²²

An enlarging body of evidence indicates a heightened risk of cardiovascular disorders after attainment of menopause. A clinical trial conducted on Indian women compared the prevalence of coronary heart disease (CHD) in pre- and post menopausal states. The evaluation unveiled the CHD prevalence to be 38% in postmenopausal women in contrast to 4% in those yet to attain menopause.²³   These findings were verified by another study conducted on post-menopausal women with suspected ischemia. The results revealed angiographic evidence of CHD in 31% (n=482) of the participants.²⁴

Need for hormonal replacement therapy: Review of current literature

Given the high prevalence of devastating health outcomes associated with menopause, interest in the therapeutic potential of hormone replacement therapy (HRT) has sparked new efforts to understand its long-term consequences. Several researchers have unraveled the potential benefits of HRT in reducing the risk of cardiovascular disease, improving quality of life and increasing longevity in post-menopausal women.²⁵   Data extracted from the Women’s health initiative trial²⁶   has corroborated the therapeutic efficacy of HRT in relieving vasomotor symptoms, treating genital atrophy, and reducing the incidence of osteoporotic fractures. In contrast, some investigators have asserted that HRT may have potential drawbacks in these women. An increased risk of venous thromboembolism (VTE) and breast cancer has been suggested in a few studies.^27,28

The contentious role of HRT after menopause has garnered considerable attention in the recent years paving the way for an in-depth risk versus benefit assessment. Evolving data now sheds new light on the potential advantages of HRT and suggests that the benefits may outnumber the risks.

Benefits outweigh drawbacks: Highlights of the Global Consensus Report 2013

Notwithstanding the evidence that HRT may have some role in potentiating the occurrence of VTE and breast cancer, emerging reports have indicated that the benefits of HRT are likely to outweigh the risks.²⁹   This may particularly hold true if HRT is initiated in women younger than 60 years or within 10 years after menopause.³⁰   It is further recommended that HRT should not be withheld due to the fear of breast cancer since its protective actions against cardiovascular disease and osteoporosis outweigh this possible risk.³¹   Dose and duration of regimens must be individualized for every patient. A comprehensive medical history must precede HRT prescription and indication should be reevaluated annually. Researchers have asserted that the magnitude of benefit of HRT can be greater than that of the risk, if dosage and duration are meticulously monitored and if individual risk factors such as the possibility of VTE, stroke, ischemic heart disease and breast cancer guide HRT prescription.³⁰

The aforementioned assertions have been verified by the Global Consensus Report 2013 on menopausal hormone therapy.³²   The report unravels that HRT is highly effective for the prevention of osteoporosis-related fractures and treatment of vasomotor symptoms associated with menopause. Information gleaned from this report also validates the efficacy of estrogen monotherapy in particular, in decreasing the incidence of coronary heart disease and all-cause mortality in women younger than 60 years of age. Use of estrogen as a single systemic agent is also preferred in women after hysterectomy. Besides, concerns of breast cancer and VTE are also well-addressed. It is suggested that the absolute risk of VTE is rare below 60 years of age. The increased risk of breast cancer is small and primarily related to estrogen-progesterone combination and its duration of use. In addition, this risk diminishes substantially on withdrawal of therapy.

Besides the above-mentioned, estrogen therapy also plays an essential role in reducing total mortality in post-menopausal women. Despite this, a decline in estrogen prescription and usage has been noted the past years, reflecting a generalized avoidance of estrogen therapy. This has led to an escalation in mortality rates among post-menopausal women. Sarrel and coauthors  33   sought to evaluate the effect of estrogen avoidance on mortality rates among hysterectomized women aged 50 to 59 years. The results showed that estrogen therapy in post-menopausal women was associated with a decisive reduction in mortality, which was largely due to a reduction in cardiovascular deaths.

Concluding remarks

Menopausal transition is a time of marked hormonal instability that may adversely impact a woman’s health outcome. With declining estrogen levels, risk factors for CHD, osteoporosis and systemic disorders become apparent. HRT is a complicated clinical issue that has been subject to in-depth risk versus benefit assessment. Novel evidence suggests that the benefits of HRT outweigh the drawbacks, provided the choice of therapy, personal risk factors and underlying medical concerns are meticulously considered.

Hormonal therapy in infertility

Infertility: An overview

Infertility is defined as the incapacity to fulfill pregnancy after a reasonable period (at least 1 year) of regular unprotected sexual intercourse.³⁴   Infertility is one of the most prevalent conditions in young adults affecting about 8-10% couples worldwide.^35,36     Epidemiological research in the past has revealed much to suggest a high prevalence of infertility in the female population.³⁷   Consequently, reproductive medicine has progressed by leaps and bounds leading to notable advances in fertility procedures for women.

The use of assisted reproductive technologies for infertile women has grown significantly. A US-based study³⁴   showed the number of women using infertility services to rise from 6,00,000 in 1968 to 2.7 million in 1995. Extensive research in the recent decades has led to the development of a bewildering variety of treatment procedures, in vitro fertilization (IVF) being the most common of them.³⁸

In vitro fertilization: New light on the role of estrogen

IVF is an advanced reproductive technology that has gained immense popularity in the recent decades. The IVF process involves fertilizing the ovum and sperm outside the mother’s body; once fertilized, the embryo is transferred into the mother’s uterus for development and delivery.³⁹   Estrogen plays a fundamental role in determining the window of opportunity for an embryo to get implanted to the uterine wall and begin development.⁴⁰   However, studies have shown endogenous estrogen levels to fall rapidly in the luteal phase of IVF cycles.⁴¹   This may adversely affect pregnancy outcomes in IVF. In addition, the importance of estrogen in controlled ovarian stimulation (COH), the primary step in IVF, is also well-recognized. Investigators have demonstrated that serum estrogen levels have a concentration-dependent effect on the pregnancy outcome, suggesting an optimal range of estrogen level for achieving a successful pregnancy. A study conducted to assess the influence of serum estrogen on COH showed the number of oocytes obtained, and consequently the pregnancy rate, to increase with increasing estrogen levels. Hence, it was deduced that estrogen concentration is an important predictor of IVF success.^42,43

In this context, the role of hormonal therapy with estradiol in IVF cycles has garnered attention. Studies have shown estradiol, particularly in combination with progesterone to enhance implantation and pregnancy rates.⁴⁴

Hormone therapy with estradiol valerate

Hormone replacement with estrogen compounds heralds a new era in boosting IVF success rates, by virtue of its multifactorial effects. Estradiol valerate is a natural form of human estrogen that has been shown to play an essential role in increasing the number of oocytes obtained during COH, aiding in implantation and optimizing pregnancy outcomes. Although data demonstrating the role of progesterone in enhancing IVF outcomes is abundant, the benefits of estradiol addition to progesterone, have been speculative.^45,46       Emerging data, however, has shed light on the clinical efficacy of estradiol -progesterone combination in IVF procedures. A study was conducted to compare the efficacy of estradiol-progesterone combination and progesterone monotherapy for luteal phase support in IVF cycles. The results unraveled that the clinical pregnancy rates were significantly higher in the combination group than progesterone only group (37% versus 12.1%, respectively).⁴⁷   Similar results were obtained in another study that demonstrated higher implantation rates with estradiol valerate-progesterone combination (22%) in women undergoing IVF cycles compared to progesterone alone (13.3%).⁴⁶

The efficacy of estradiol valerate in patients showing poor response to ovarian stimulation is also well-established. Studies reveal that poor response during COH may result in critically low conception rates. However, such patients, when subjected to estradiol valerate therapy show improved overall IVF outcomes. A study conducted by Chang and coauthors⁴⁵   corroborated this clinical finding by showing the patients treated with luteal estrogen to demonstrate higher number of retrieved oocytes compared to standard GnRH antagonist protocol (4.5 ± 2.9 vs 3.2 ± 1.9). In addition, greater number of normally fertilized embryos (2.9 ± 2.1vs 2.3 ± 1.9), and increased prevalence of good quality embryos (51.2% vs 25%; p = 0.047) were noted at the end of the study.

These evidences endorse the crucial role of estradiol valerate therapy in improving overall IVF outcomes.

Concluding remarks

In vitro fertilization is an advanced reproductive technology widely employed in infertility clinics. Studies suggest that hormonal therapy is paramount to achieving desirable IVF outcomes. The efficiency of progesterone therapy in improving IVF success rates is undisputed. Evolving data, however, demonstrate the clinical efficacy of addition of estradiol valerate to progesterone in enhancing implantation and conception rates during IVF procedures.

Choosing the right estrogen: Benefits of estradiol therapy

A basic clinical understanding of the types and regimens of available estrogen preparations is imperative for initiation of the correct estrogen therapy. Conjugated equine estrogens (CEEs), synthetic esterified estrogens, ethinyl estradiol-containing preparations and pure 17-beta estradiol-containing products are commonly used. Factors that influence the choice of regimen include underlying medical concerns, risk factors and personal preferences of the individual.⁴⁸

Conjugated equine estrogens represent the earliest commercial preparations available for postmenopausal hormone therapy. Although, these compounds have been used for several decades, uncertainties in the characterization of their properties cast doubt on their safety. Investigators have unraveled that their metabolites exhibit toxic properties with carcinogenic potential through the synthesis of quinones. Besides, the conception that conjugated equine extract confers benefits in post-menopausal women by virtue of its mixture of components has weak scientific evidence.⁴⁹

On the other hand, estradiol valerate, an esterified form of natural 17beta-estradiol, is the most potent endogenous human ovarian estrogen with a reasonably acceptable safety profile. It undergoes hydrolysis to form estradiol soon after oral administration.⁵⁰   The compound has been available since the 1970s in both oral and parenteral forms.⁵¹   However, its oral micronized form represents an advance in the management of climacteric manifestations. It exhibits a favorable pharmacokinetic profile and is rapidly absorbed from the gastrointestinal tract.⁵²

A strong body of evidence demonstrates the excellent efficacy of estradiol valerate in relieving menopausal symptoms. A study conducted to test the effectiveness of the drug in ameliorating vasomotor symptoms showed 91% reduction in moderate to severe hot flushes in menopausal women.⁵³   These findings were confirmed by another study that showed 95% patients (n=369) with estrogen deficiency and related menopausal symptoms to attain satisfactory symptomatic relief after cyclic administration of oral micronized estradiol (figure 5).⁵⁴   The favorable effects of this formulation on bone health are also well-recognized. Prestwood et al⁵⁵   demonstrated that micronized estradiol, when administered in low doses in post-menopausal subjects, increased bone density of the hip, spine, and total body, and reduced bone turnover, thereby preventing osteoporosis. In addition, there were no reports of breast cancer during the study and associated adverse events were trivial.

These data validate the safety and efficacy of the estradiol compound in post-menopausal women.

Besides the choice of formulation, the timing of hormone therapy initiation also holds critical importance in achieving the desirable results.56   Grodsteinet al57   have previously demonstrated that the timing of hormone therapy initiation in relation to menopause onset or age influences coronary risk. To delve further, the Early versus Late Intervention Trial with Estradiol (ELITE)58   was conducted with focus on the differential effect of hormone therapy on retarding atherosclerosis progression according to the timing of commencement of therapy. The women were divided into two groups; mean age of the first group was 55 years and that of the second group was 65 years. Patients were randomized to receive estradiol, 1 mg given orally each day, or placebo. The results showed that the women in the first group, who were in early menopause, had a slower progression of atherosclerosis, as measured by carotid intima media thickness (CIMT), than those who received placebo. On the other hand, the older women did not show such a change.

Estradiol versus other estrogens: Evidence-based comparison

The superiority of estradiol valerate over other estrogen preparations such as conjugated equine estrogens has been evidenced by several researchers. A trial was undertaken to compare the metabolic and endocrinological effects of estradiol valerate-containing regimen and conjugated estrogen-containing regimen in a post-menopausal setting. The results demonstrated a significant reduction in low-density cholesterol (LDL) with estradiol regimen in contrast to an increase in LDL with the comparator. In addition, a decrease was observed in total plasma cholesterol with both the therapies, but was substantially greater with the former regimen. It was concluded that a greater improvement in lipid parameters, compatible with decreased cardiovascular risk was conferred by estradiol valerate therapy.⁵⁹   A very recent study substantiated these findings by showing women on conjugated estrogen therapy to be at a greater risk of venous thrombosis and myocardial infarction compared to those on estradiol therapy.⁶⁰   Besides, investigators have shown that unlike conjugated equine estrogens, estradiol valerate brings about a noteworthy improvement in endothelial function by reducing plasma levels of endothelin-1 in post-menopausal women at risk of CHD, which further attests to the superior cardioprotective efficacy of the drug.⁶¹

In addition to the above-mentioned, the superiority of estradiol formulations is also elicited in terms of its milder impact on the breast tissue compared to conjugated estrogens.⁴⁴   Use of conjugated estrogens is believed to result in an undesirable increase in mammographic density in post-menopausal women. Mammographic density is positively associated with breast cancer risk. Studies, however, have shown that only a minority of patients on estradiol valerate therapy show increased mammographic density, while those on conjugated estrogen therapy demonstrate a statistically significant increase that is sustained over a 2-year period.^62,63

The comparative effects of the two estrogen compounds are summarized in table 1.

Concluding remarks

Micronized estradiol, is a natural form of estrogen that displays a multitude of beneficial effects in women with climacteric symptoms. Information available from several studies provides persuasive evidence in favor of its superiority over other estrogen formulations.

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