Estrogen is one of the female sex hormone. There are three major endogenous estrogens namely estrone (E1), estradiol (E2), and estriol (Fig. 1). Among them E2 is the most potent and the most prevalent one. There are a large number of synthetic estrogen preparations which might be steroidal or nonsteroidal. Various preparations of synthetic estrogens that are clinically used include E2 valerate, E2 cypionate, E2 benzoate, E2 undecylate, and polyestradiol phosphate. Ethinyl E2 is the most widely used synthetic analog of E2.
ROUTES OF ADMINISTRATION
There are various routes of estrogen administration namely oral, vaginal, intramuscular, and patches or gel. Among these, oral route is the simplest and well-tolerated mode of administration. E2 form after oral administration undergo extensive metabolism in the intestinal mucosa and in liver and is converted to E1 and estrone sulfate (E1S). The E1 level gradually increases after oral administration and become higher than E2. While in transdermal preparations significantly less amount of E2 is converted to E1.
After oral or parenteral administration, E2 valerate, the synthesis compound contained in various commercially available preparations, is completely converted into the natural substances 17p-E2 and valeric acid. The 17 beta-E2 produced on cleavage of the ester behaves in the organism like the endogenous steroid hormone. E2 valerate and 17 beta-E2 are virtually dose equivalent. No differences in the spectrum of action of the estrogen and its ester have been found either in animal experiments or man. The pharmacokinetic behavior and the biotransformation of the 17p-E2 originating from E2 valerate are no different from those of natural 17 beta-E2. Differences of practical significance exist in respect of the quantitative effect of E2 valerate following oral and intramuscular administration. 4 mg E2 valerate administered intramuscularly is therapeutically sufficient for a period of 2–4 weeks producing a depot effect. While 2 mg daily oral preparation need to give for 3 weeks to produce the same effect.
Following parenteral administration of E2 valerate, 17% E2 becomes completely bioavailable in man. Because of the delayed release of the steroid ester from the intramuscular depot referred to earlier the blood level does not reach its maximum for 3–5 days, after which it falls slowly, with a half-life of 4–5 days. A distinct increase in the 17p-E2 level can be achieved over a period of about 14 days, with an intramuscular injection of 4 mg E2 valerate.
When compared with the parenteral route of administration, the bioavailability of the estrogen after oral administration is greatly limited due to the metabolic process in the gastrointestinal tract, the intestinal wall, and the liver (during the first passage). As the metabolites are much less estrogenic than unchanged 17 beta-E2, higher dose E2 valerate must be used for oral medication than for parenteral administration.
METABOLISM AND ELIMINATION
The 17 beta-E2 arising in vivo from E2 valerate behaves in the organism behaves like endogenous 17 beta-E2 and is subject to intermediate metabolism. Regardless of the route of administration, not only 17 beta-E2 but also E1 and estriol occur in human plasma following administration of E2 valerate. However, the plasma concentration of the free steroids, with their differing potency, is low in comparison with the concentration of their 5conjugates. In man the metabolites of 17 beta-E2 are primarily eliminated by the kidneys regardless of the route of administration, the vast majority of the metabolites arising from E2 valerate (80%) were found in the urine.
USES OF ESTROGEN PREPARATIONS
The clinical uses of E2 include for synchronization and preparation of endometrium in frozen embryo transfer (FET) cycle, treatment of thin endometrium and as a luteal phase manipulator in poor responders prior to stimulation to increase the number of oocytes.
Now FET is one of the most common components of assisted reproductive technology (ART). The FET cycle is having success rate in par with the fresh embryo transfer cycles. Implantation is one of the most important components of successful ART which depend on three factors including embryo quality, endometrial receptivity, and synchrony between embryo and endometrium. The endometrial receptivity during the implantation depend on both progesterone and estrogen level. The role of progesterone in luteal phase support has been well documented, while the exact role of estrogen in luteal phase is not clear. Some investigators have advocated supplementing E2 during the luteal phase of ART cycles. Subsequently, meta-analyses argued against this practice as being not justified based on results. The debate persists; however, some groups prefer estrogen for luteal phase support after ET while others do not.
Estradiol pretreatment is mandatory; however, for priming endometrial receptivity for FET. Decades of ART and donor egg activity have revealed that E2 administration is relatively simple, effective, and extremely forgiving. Various regimens are proposed for endometrial preparation in FET. E2 supplementation causes the proliferation of endometrial cells and causes endometrial thickness. The E2 supplementation not only causes endometrial thickening but also induction of appropriate progesterone receptors to improve the endometrial receptivity. The daily oral administration of 4–8 mg of E2 reproduces the serum levels and peripheral effects of E2 as seen in the menstrual cycle. The excess liver exposure due to the first liver pass effect inherent to oral administration may cause problem in certain individuals, notably in women at higher risk of venothromboembolism accidents. In these individuals, E2 should not be administered orally if at all possible and/or preventive medication (e.g. low molecular weight heparin) should be provided simultaneously.
ORAL FORMULATIONS USED IN INFERTILITY PRACTICE
Oral preparation, E2 valerate is subjected to extensive first pass metabolism and gets converted to E1, estriol, and 17 beta-E2. There are various regimens used for estrogen supplementation. Usually used regimen is variable low-dose step-up regimen starting with E2 valerate 2 mg once daily for 2–4 days 6followed by twice daily for 4 days and then stepped up to thrice daily for 4 days. Progesterone is added once the endometrial thickness reaches 7 mm or more. Some prefer using transdermal patches for endometrial preparation.
The intense liver metabolism of orally administered E2 renders this route of administration vulnerable to the effect of enzymatic inductors, such as psychotropic medications. Women exposed to enzymatic inductors are notably resistant to the effect of oral E2. In these cases, it is preferable to revert to nonoral administration.
Estradiol valerate, a prodrug of E2 is an E2 ester. It can be considered as an agonist of estrogen receptors. The affinity of E2 valerate for estrogen receptors is approximately 50 times lower than that of E2. Micronized E2 is rapidly and completely absorbed on oral administration.
Estradiol hemihydrate is the micronized form of 17 beta-E2, the most potent naturally produced estrogen. E2 hemihydrate diffuses through the cell membrane and binds to and subsequently activates nuclear estrogen receptor.
OTHER ROUTES OF ADMINISTRATION
Apart from the oral mode of administration, other routes of administration include intramuscular, transdermal, and vaginal. All these routes help to avoid first pass liver metabolism which is one of the main limitation of oral mode of administration. But on comparing the pregnancy rates with different modes of administration all the preparations achieved almost similar rates. Among these, commonly used regimen is the transdermal mode. Transdermal administration of E2 can be done using skin systems or gels. In ART, skin systems have been generally preferred because they allow us to more precisely adjust the administered dose. Basically, it suffices to choose the doses of E2 normally produced by the ovary (mean production rate of 0.2 mg/24 hours) for reproducing similar blood levels and peripheral effects of E2. During nonoral administration of E2, E1 levels remain in the physiological range: E2/E1 >1. By contrast, E1 levels are nearly 10 times higher than E2 following oral administration. To this day; however, no detrimental effects have been recognized regarding the pharmacological levels of E1 induced by oral E2 administration. The transdermal systems have been found to be possibly weakly effective in overweight and/or obese women, in whom oral administration will be preferred. Finally, transdermal systems may become poorly effective in case of hot and humid weather. One practical element for enhancing the adhesion of transdermal skin systems consists of wiping off skin grease with a tissue. The advantage over oral form is that it attains good serum concentration. Its disadvantage is that it might prove to be slightly inconvenient because several patches have to be simultaneously used to achieve and maintain serum concentration. One of the randomized controlled trial (RCT) comparing the use of E2 patches with the oral E2 in FET cycles found no difference in FET cycles.7
Estradiol can also be administered vaginally. While especially designed creams exist in the USA, numerous investigators have simply given oral tablets vaginally. This, however, results in extremely high serum levels, but without further hepatic impact than is encountered with oral tablets. Vaginal E2 can be a valuable alternative, particularly for women whose endometrial response to E2 appears impaired. With transvaginal estrogen it can attain high serum and endometrial concentration and is considered as a good alternative to oral preparation. Usually used preparation includes hemihydrate. Many studies have shown that when hemihydrates is combined with clomiphene, the endometrial thickness improves but with no effect on pregnancy rates. Similarly, data from egg donation programs, in which oral and vaginal micronized estrogen administration were compared, proved a valid alternative in safety terms. But this is not the only alternative, as possible interactions between estrogens and progesterone may occur at the vaginal mucosa, as well as a drop in serum E2 concentrations in the luteal phase, or even a more marked difficulty of progesterone compensating higher uterine contractility due to increased E2 concentrations. These phenomena might have a negative impact on embryo implantation. The vaginal route may improve patient tolerance and symptoms, but one RCT have not shown any improvement in endometrial thickness, not even with other cointerventions, although the study sample was limited.
OTHER USES OF ESTROGEN
Another application of estrogen supplementation is as part of treatment of thin endometrium. One of the treatments proposed is progressive step up increase in the dose that stimulates a natural cycle. So patients can start with high dose (6–8 mg or up to 16 mg) continuously from cycle day 1, unless the tolerance is poor. In general, 2 mg suffice to block the hypothalamus–pituitary–ovary axis so there is no need to add gonadotropin-releasing hormone analogs in the luteal phase as this may compromise endometrial vascular flow and proliferation. Another treatment suggested for thin endometrium is the use of extended use of estrogen. However, most studies come from the FET cycles. Chen et al. have evaluated the effect of extended administration of E2 valerate during controlled ovarian hyperstimulation cycles and found that mean endometrial thickness in the study group increased significantly from 6.7 mm to 8.6 mm following an extended estrogen therapy for 14–82 days. The pregnancy rate in the study group was significantly higher than that in the control group (38.5% vs. 4.3%). Embryo implantation is undoubtedly one of the most critical steps in the ART process. Implantation success depends on the cross talk between embryo and endometrium. A critical level of estrogen is essential in regulating the window of uterine receptivity for implantation. Oral estrogen preparations are preferred due to their efficacy and ease of use (Table 1).8
CONTRAINDICATIONS FOR ESTROGEN THERAPY
- History of breast cancer
- History of endometrial cancer
- Severe active liver disease
- Thromboembolic disorder
- Undiagnosed vaginal bleeding
- Migraine headache
- Lung embolism
- Increased risk of cardiovascular event
- Protein C deficiency
SIDE EFFECTS OF ESTROGEN THERAPY
- Abdominal bloating
- Break through bleeding
- Breast tenderness/pain
- Freckles or darkening of facial skin (melasma)
- Menstrual pattern change
- Achache H, Revel A. Endometrial receptivity markers, the journey to successful embryo implantation. Hum Reprod Update. 2006;12(6):731–46.
- Cetinkaya K, Kandanali S. The effect of administering vaginal estrogen to clomiphene citrate stimulated cycles on endometrial thickness and pregnancy in unexplained infertility. J Turk Ger Gynecol Assoc. 2012;13:157–61.
- Chen MJ, Yang JH, Peng FH, et al. Extended estrogen administration for women with thin endometrium in frozen-thawed in-vitro fertilization programs. J Assist Reprod Genet. 2006;23:337–42.
- Fanchin R, Righini C, Schönauer LM, et al. Vaginal versus oral E(2) administration: effects on endometrial thickness, uterine perfusion, and contractility. Fertil Steril. 2001;76:994–8.
- Kuhl H. Pharmacokinetics of estrogen and progesterone. Matuuritas. 1990;12(3):171–97.
- Serna J, Cholquevilque JL, Cela V, et al. Estradiol supplementation during the luteal phase of IVF–ICSI patients: a randomized, controlled trial. Fertil Steril. 2008;90:2190–5.
- Shen MS, Wang CW, Chen CH, et al. New horizon on successful management for a woman with repeated implantation failure due to unresponsive thin endometrium: use of extended estrogen supplementation. J Obstet Gynaecol Res. 2013;39:1092–4.