Estradiol in non-oral hormonal contraception: a “long and winding road”

KEYWORDS:

• Combined hormonal contraceptives
• ethinyl-estradiol
• estradiol
• venous thromboembolic events
• transdermal
• transvaginal
• vaginal ring
• nestorone

1. Introduction

The pill [combined oral contraceptive (COC)], with around 140 million of users worldwide, is the most popular method of contraception and the most used ‘chronic therapy’ by women before the age of 40, period of life in which they are generally healthy.

The traditional COC has exclusively contained ethinyl-estradiol (EE) in decreasing doses for about 50 years. The introduction of estradiol (E2) alongside EE started in 2009 by oral route, with the original aim of reducing the metabolic impact and the possible risk of cardiovascular events associated with COC use [1]. As a matter of fact, the 17α-ethynyl group of EE prevents oxidation of the carbon 17β position by 17β-hydroxysteroid dehydrogenase, in contrast to E2: for this reason, EE has much stronger relative estrogenic activity on some liver proteins, up to 500–600 times greater than E2 [2].

Finally, a recent observational study of a cohort of more than 50,000 new COC users between Europe and the USA [the International Active Surveillance study ‘Safety of Contraceptives: role of Estrogens’ (INAS-SCORE)], indicates, though with important limitations of real-world data, that the risk of venous thromboembolism (VTE) and other cardiovascular events is similar and possibly lower with the use of E2 containing pills if compared with EE [3].

Furthermore, the introduction of parenteral ways of administration (intravaginal and transdermal) has further expanded the comfort of use and compliance with combined hormonal contraceptives (CHCs). Until now, intravaginal and transdermal contraceptives available on the market have contained exclusively EE. Just in the last years, there is an increasing interest in the study of the use of E2 by parenteral ways. This is very interesting because it could reduce the risks of CHCs even more. This is because of the evidence that transdermal E2 in postmenopausal women is safer than all oral estrogens in terms of VTE risk [4,5]. But at what point are we with the contraceptive parenteral formulations containing E2?

2. Intravaginal

In October 2001, the US FDA firstly approved the use of NuvaRing® produced by Organon (Oss, The Netherlands), a thin flexible plastic ring that women can flatten like a rubber band and insert once a month into the vagina as CHC, containing EE and etonogestrel (ETN): this was considered as one of the best inventions in health science in that year for the newspaper ‘Time’. Despite this important initial interest and also an excellent subsequent market success, over the last 17 years, there has not been a substantial evolution of this product. In 2017, a new ring containing the same hormones and at the same dosage came out on the market [6]: the main improvement was the new polymer composition that provides the new ring with more stability and gradual hormonal release during the first hours of use. Only in the last year, 3 trials have been published using new rings with E2 [7–9].

Duijkers et al. randomized 666 healthy women (18–35 years old) [7] in a Phase II study for three cycles of treatment to six rings with an average daily release rate of 300 µg E2 and various doses of either ETN (75, 100 or 125 µg/day) or nomegestrol acetate (NOMAC 500, 700, or 900 µg/day) in comparison to the traditional NuvaRing®.

Ovulation inhibition was observed in all groups. All investigational rings provided good cycle control, with the E2/ETN 300/125 µg/day group exhibiting the best cycle control based on the lowest incidence of unscheduled bleeding and absence of scheduled bleeding. However, non-inferiority to NuvaRing® with respect to the incidence of unscheduled bleeding was not achieved for any of the new E2 ring groups.

Two important considerations can be obtained from this trial:

2.1. Dose of E2

The dose of E2 requested in this study [7] by vaginal route is 300 µg, the corresponding figure by oral route are 1.5 mg of E2 or 2–3 mg of its ester E2 valerate: the dose is reduced between one fifth and one tenth. The vaginal route achieves a far higher E2 levels and E2/estrone ratio in comparison to oral, around 10 times greater, with a daily dosage of 1 mg E2 resulting in levels of 500 pg/mL (a not physiological estrogenic serum level) by vaginal and 30–50 pg/mL by oral [1]. In [7], the median serum E2 levels remained between 50 and 100 pg/mL during all different treatment groups during E2 vaginal administration.

2.2. The effect on sex hormone binding globulin (SHBG) levels

The prothrombotic effect of CHCs can be related to the total estrogenicity of the combination, that rises with increasing the estrogenic potency but decreasing with antiestrogenic activity of the combined progestin. SHBG, being both affected by estrogenic potency and the androgenic activity of progestin and directly related to change in activated protein C (APC) sensitivity ratio, could be considered as a marker for predicting VTE risk in CHCs users [10,11]. SHBG levels can also influence the serum concentrations of free E2, the only biologically active hormone. In this study [7], SHBG levels decreased from baseline in all investigational E2 ring groups. A similar effect was described when the progestin components were administered alone without any estrogenic component [10], suggesting the lower hepatic impact of E2 rings even compared to E2-based COCs, and much lower impact than EE-based CHCs.

The second trial [8] was another Phase II randomized, placebo-controlled, multicenter, double-blind study: subjects with primary dysmenorrhea (n = 439) were randomized to one of five treatment groups: four hormonal rings releasing 300 μg of E2 daily along with 700 μg or 900 μg of NOMAC or 100 μg or 125 μg of ETN, and one placebo ring. The decrease of dysmenorrhea in all four E2 ring groups in comparison to placebo was statistically significant, bearing a greater reduction than placebo in nonsteroidal anti-inflammatory drugs use.

In the third dose-finding study [9], a new progestin molecule was combined to E2, nestorone (NES) or segesterone. This is a potent 19-nor-progesterone derivative when given parenterally, with the highest antiovulatory activity among synthetic progestins associated with a neutral androgenic activity and metabolic profile. NES is not active orally, but it is rapidly absorbed through the vaginal mucosa. A prospective, double-blind, randomized study was carried out on 197 women to evaluate the pharmacokinetics during a three cycles treatment with rings containing E2 10, 20 or 40 µg/day and NES (200 µg/day). While the levels of NES were similar during treatment with the different rings, for E2, the 2-h Cmax was significantly higher with the 20 µg/day ring (mean 390 pg/mL) in comparison to 10 µg/day ring (189 pg/mL) and 40 µg/day (189 pg/mL). In this study the vaginal doses of E2 used were further reduced to one-tenth in comparison to [7]: the median serum E2 levels remained under 35 pg/mL during all different group treatments. However, no data about cycle control with these different rings were presented from this trial.

Though the encouraging preliminary data with these new rings, Organon (Oss, The Netherlands) was taken over by Merck Sharp & Dohme (Readington, New Jersey), which did not take much interest in the field and even managed to discontinue the whole program in the middle of Phase III trials: for this reason, we cannot expect in a short period of time to have a new vaginal ring based on these compounds.

3. Transdermal

The progestin NES is rapidly absorbed also through the skin. For this reason, combinations of E2 and NES are under investigation not in a patch as the one EE-based currently on the market, but using an advanced transdermal deliver gel contraceptive one administration daily. The impact of E2 on liver proteins and coagulation factors has been shown to be minimal when administered transdermally in postmenopausal women [12].

A randomized, open-label, three-cycles, cross-over study [13] has been conducted on 16 subjects to evaluate the effects of different doses of E2/NES transdermal gel (low dose: 0.5 mg+1.5 mg, medium dose: 1.0 mg+3.0 mg or high dose: 1.5 mg+4.5 mg) on ovulation inhibition, suppression of follicular growth and pharmacokinetic parameters to determine the lowest effective transdermal gel doses to inhibit ovulation in 90–95% of cycles. Ovulation was inhibited in all dose groups, with more episodes of unscheduled bleeding reported for the lowest doses (0.5 mg+1.5 mg). The medium dose (1.0 mg+3.0 mg) represented in this study the lowest effective dose for suppressing ovulation and follicular development and it was proposed for future clinical development. By this route of administration, the studied E2 doses were therefore about one half compared to those used orally [2]. However, the serum levels of E2 achieved in this study (around 110–165 pg/ml) were higher than during vaginal [7,9] and also oral administration [14,15], with no modification of SHBG levels.

4. Conclusion

To conclude, the non-oral administration route of E2 in hormonal contraception is possible, both intravaginal and transdermal: it could further reduce the amount of E2 required to give a satisfying cycle control, in particular by the vaginal route. This innovation would limit the metabolic impact, and the risks associated with CHCs use even more in the next future. Unfortunately, due to commercial interests, Phase III trials examining these products have been temporarily stopped.

Declaration of interest

G Grandi received honoraria for sponsored lectures and participation in advisory boards from Teva/Theramex and Bayer AG. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.