Emilia Huvinen, Elina Holopainen, Oskari Heikinheimo

@e_huvinen @OHeikinheimo

Synthetic progestins are commonly used for a wide spectrum of conditions along a woman’s life. They are essential in the daily work of doctors treating women of all ages – both general practitioners and gynecologists. Indications stretch from contraception and postponing menstruation to treatment of heavy uterine bleeding and as a part of hormonal replacement therapy.

Different progestin molecules have all distinct properties based on their receptor binding capacities, and this may have clinical significance. Norethisterone (NET) and its acetate (NETA) are among the most used progestins in Europe. NET and NETA differ from other progestins in that they are partially converted to ethinyl estradiol (EE). As use of EE is associated with some adverse outcomes such as thromboembolic events, we wanted to review the literature concerning potential pros and cons of NET/NETA use.

What we did?

We performed a medical literature search in PubMed and OvidMedline searching for potential research on NET/NETA, its conversion to EE, and specific clinical characteristics.

What we found?

Earlier works by Kuhnz and Chu have demonstrated that NET converts to considerable amounts of EE. This means that 10-20mg of NET corresponds to a combined oral contraceptive pill containing 20-30 micrograms of EE, being potentially of clinical significance, especially to risk groups with contraindications to EE use.

However, it should be remembered that this is dose-dependent. NET doses used in contraception (0.35mg/day) or in postmenopausal hormone therapy (0.5 – 1 mg/day) are far from the therapeutic doses typically reaching 10-20mg/day. NET is a very potent progestin with a strong effect on the endometrium making it a great choice when treating endometrial hyperplasia of heavy menstrual bleeding. It has beneficial effects on bone mineral density and neutral or beneficial effects on elements of cardiovascular health such as lipids, glucose metabolism, and body composition. On the other hand, NET also increases the risk for thromboembolic events; this is especially evident along therapeutic doses but it is also slightly increased in postmenopausal hormone therapy. NET also seems to have a more unfavorable effect on the breast tissue, detected as a higher risk for breast cancer in long-term use of more than 3 years.

One of the common contraindications to EE use is migraine with aura, which is a rather common neurological concern of women. It is associated with a higher risk of stroke but oral contraceptive pills containing EE, increase this even further. We are concerned that NET might also be harmful for these women. However, there are no studies assessing the use of therapeutic NET doses in high risk groups, such as women who suffer from migraine with aura. Other high-risk groups might include women with other intrinsic risk factors for thromboembolic events and those with obesity, who simultaneously are at higher risk of endometrial hyperplasia, but there are no studies assessing these risk groups either.

What next?

We hope that future studies will assess the use of NET in specific high risk groups. Until then, we suggest special consideration when treating women with migraine with aura, obesity, and higher risk for thromboembolic events. On the other hand, one should remember that NET is a very useful and effective progestin and there is no elevated risk, for example, in contraceptive use due to the lower doses. We suggest that short-term use, even with therapeutic doses for heavy or anovulatory menstrual bleeding, is safe for all women.

Norethisterone and its acetate – what’s so special about them? by Emilia Huvinen, Elina Holopainen, Oskari Heikinheimo was published in BMJ Sexual and Reproductive Health