Endometrium

During the menstrual cycle, the estrogen-primed endometrium is converted from proliferative to secretory histology following exposure to progesterone. The therapeutic use of progestogens utilises this property, and includes indications such as treatment of abnormal uterine bleeding, induction of therapeutic amenorrhea, and postponing menstruation. Additionally, progestogens are effective in treating endometriosis. The typical daily dose of NET used for controlling uterine bleeding is between 10 and 20 mg, in comparison to the 0.5–1 mg required for ovulation inhibition in CHCs and the 0.35 mg used in progestogen-only contraceptives.

NET has a pronounced effect on the endometrium.2 The dose needed for endometrium transformation is 30–60 mg per cycle—significantly less than the commonly used daily dose of 10–15 mg for 10 days.1 In postmenopausal HT, transdermal NET in combination with estradiol also appears to be effective; the risk of endometrial hyperplasia was undetectable following sequential administration of 140–400 µg/day NET and in continuous treatment with 170–350 µg/day.15 When compared with MPA in a randomised controlled trial (RCT), the daily use of 1 mg NET resulted more often in endometrial atrophy (73%) than treatment with 2.5 mg MPA (32%).2 In the treatment of endometrial hyperplasia, daily doses of 15 mg NET, 10 mg MPA, and 15 mg lynestrenol (10 days/cycle) were equally effective.16 In continuous combined postmenopausal HT, the use of NET seems to result in the lowest rate of dysfunctional bleeding.17

Risk of thrombosis

The estrogen component of CHCs was long suspected to be the main culprit for the associated thromboembolic complications. The progestogenic component, however, plays an additional role in modifying this risk. According to a meta-analysis, the second-generation progestogens, such as levonorgestrel, in combination with EE demonstrate the lowest risk of thrombosis (risk ratio (RR) 2.8 compared with non-use). For the first-generation progestogens, such as NET, the corresponding RR is 3.2, and for the third- and fourth-generation progestogens the RR is 3.8.7

When comparing progestogen-only contraceptives, none of the studied compounds activated the hemostatic system or increased the risk of venous thromboembolism (VTE).18 A recent systematic review evaluated the thromboembolic risk of progestogen-only contraception in high-risk groups such as smokers, women with hypertension, or with a family history of thrombosis, and found no increased risk of VTE with any of the progestogens studied. The use of injectable MPA, however, surprisingly increased the risk of VTE (odds ratio (OR 3.0).19 The reason for this remains unclear. Hypothetically, women using injectable contraception might have a common underlying feature increasing their susceptibility to VTE.

In postmenopausal HT, the type of estrogen and its administration route additionally influence the thrombotic risk. The transdermal route of HT administration is associated with lower risk, and oral estradiol is associated with a lower risk compared with oral conjugated equine estrogen (CEE). When comparing oral NET and MPA with similar estrogen dose and route of administration, NET showed a slightly higher risk of VTE.20 The use of transdermal estrogen, even when combined with progestogens, failed to elevate the risk.5

The World Health Organization (WHO) collaborative study21 22 assessed the risk of VTE associated with therapeutic use of progestogens, typically used in higher doses than in contraception. Although the number of patients was limited, the study suggested that progestogen therapy is associated with an elevated VTE risk. The characteristics of women using therapeutic progestogens and the underlying conditions might naturally influence this risk. However, after adjusting for cardiovascular disease, diabetes, and smoking, the risk of VTE remained increased (OR 5.9). Furthermore, a register-based study22 evaluated the VTE risk associated with contraceptive and therapeutic use of progestogens, and demonstrated an increased VTE risk during therapeutic (RR 5.3 (1.5–18.7)), but not during contraceptive, use (RR 1.3 (0.3–6.8)) of progestogens. Unfortunately, neither of these studies performed subgroup analysis according to the type of progestogen.

In conclusion, contraceptive use of NET in combination with EE seems to slightly increase the risk for VTE compared with second-generation (ie, levonorgestrel-containing) CHCs. Preparations for postmenopausal HT containing NET and transdermal estradiol do not show such an increase. However, in progestogen-only therapy the possibly increased thrombogenic profile of NET requires attention. Thus, concerning the risk of thrombosis, it has been suggested that therapeutic doses of NET should be considered similar to CHCs containing both estrogen and progestogen.23

Breast cancer

The risk of breast cancer is a common concern during the use of HT for menopausal symptoms. This increased risk has been associated especially with the progestogen component of HT, increasing with longer duration and continuous progestoen intake.24

When comparing the effects of NETA, MPA, and dienogest in vitro, either alone or in combination with estradiol, they similarly stimulated the growth of cancer cells. Conversely, dydrogesterone, tibolone, and natural progesterone stimulated apoptosis.25 When tested in vivo and evaluated using fine-needle biopsies from breast tissue, 3 months’ use of 1 mg NET in combination with 2 mg estradiol resulted in a four-fold increase in breast cell proliferation. A similar increase was detected when using dienogest in combination with estradiol.26

In a Finnish register-based study, however, there was no increased risk of breast cancer after 3 years of HT use, but the risk was significantly increased after 5 years of use.27 Lower risk was detectable among users of sequential HT compared with continuous use of progestogen. Additionally, the breast cancer risk was significantly higher among users of NETA (standardised incidence ratio (SIR) 2.03) compared with that of MPA (SIR 1.64). However, these results are from large observational studies and to our knowledge there are no RCTs comparing different progestogens.28

Bone

Bone density is strongly associated with female hormones as estrogen reduces bone remodelling and resorption, and maintains bone formation. In a placebo-controlled trial, the use of NET together with estradiol resulted in increased forearm bone mass and spinal bone mineral density (BMD).29 This effect was dose-dependent and related to both the estrogen and NET doses.

The use of NETA was also associated with decreasing markers of bone resorption and maintaining similar bone formation parameters further suggesting the stimulatory effect of NETA on bone formation.30 In a 6-month study comparing HT with NETA/estradiol, tibolone, and MPA/CEE, all regimens resulted in similar positive effects on BMD.31 However, a recent 2-year follow-up study suggested that compared with MPA, NETA has a more pronounced effect on BMD and fracture protection.32

Cardiovascular health and metabolism

Overall, the incidence of cardiovascular disease is lower among women before menopause than among men. This presumably relates to estrogen, which improves lipid balance, body composition, insulin resistance, and endothelial function, as well as reducing coagulation and inflammatory response.33

After menopause, progestogens in HT seem to antagonise the positive influence of estrogen on cardiovascular health. The androgenic and estrogenic properties of NET result in a combined outcome lowering both high-density lipoprotein (HDL) and low-density lipoprotein (LDL), as well as triglycerides, but maintaining the HDL/LDL ratio.34 When comparing different progestogens, progesterone, dydrogesterone, and nomegestrol acetate have neutral effects on lipids; drospirenone has positive effects, whereas the results concerning MPA are still controversial.34

Less is known about the effects of progestogens on glucose metabolism, although it seems rather neutral. A recent review on CHCs containing different combinations of estrogens and progestogens concluded that studies are small, are performed often in a healthy normal-weight population, and thus the results remain inconclusive.35 Few studies are suggestive of NET having a neutral or favourable effect on glucose regulation.31 36 Additionally, there is a paucity of studies evaluating the metabolic effects of progestogens among women with pre-existing diabetes or other conditions with marked insulin resistance such as polycystic ovary syndrome.

In addition to lipid and glucose metabolism, body composition also relates to cardiovascular health. The use of HT seems to inhibit the age-related increase in body fat percentage and to decrease the deposition of metabolically more active visceral adipose tissue.37 38 These effects did not differ between women using HT preparations containing either NETA or MPA.39

In conclusion, NET seems to have neutral or favourable effects on cardiovascular health.

Cognitive function and mood

The use of gynaecological hormonal therapies has been associated with psychological side effects such as mood swings, anxiety, and depression, and the biggest culprit has been the progestogen component. The Women's Health Initiative (WHI) study raised a concern about possible negative effects of HT on cognitive function; the effects of progestogens on memory and mood seem to depend on the timing of exposure and the age of the woman.40 HT with NET and estradiol valerate showed only minor effects on memory and attention,41 whereas an another study demonstrated more activation in the visual memory cortex in users of NET and EE.40 An RCT assessing HT with either NETA, MPA, dydrogesterone, or nomegestrol acetate in combination with estradiol found that none of these progestogens had an effect on depression. However, the use of preparations containing dydrogesterone and MPA reduced anxiety.42 Another placebo-controlled study assessed symptoms typical of premenstrual syndrome and showed that NETA in combination with estradiol had a dose-dependent effect on increasing depression, anxiety, and irritability.43 Ultimately, the results concerning the psychological side effects of NET remain inconclusive.

Migraine

Migraine is a common neurological disorder affecting approximately 15%–18% of women of fertile age in Europe and North America. The occurrence of migraine attacks is often hormone-related. Altogether 10%–15% suffer from 'classic migraine' with a related aura. Aura refers to a variety of neurological symptoms occurring before the onset of headache, such as visual disturbances or even numbness, tingling, or weakness on one side of the body, lasting for a maximum of an hour. Migraine with aura (MwA) is associated with a 2-fold risk of stroke. Having more than 12 auras annually further increases this risk (OR 10.4).44

MwA is an established contraindication to the use of CHCs. Weak evidence suggests a 2- to 4-fold higher risk of stroke among women with MwA and CHC use, but studies have not differentiated between the distinct steroidal compounds.45 According to a recent register-based study, common migraine is also associated with an elevated stroke risk, but it is lower than that associated with MwA. The use of CHCs among women with MwA increased the risk even further (OR 6.1).46 A Cochrane review demonstrated an increasing risk of stroke with increasing EE doses: lowest risk (OR 1.6) was associated with the use of 20 µg EE-containing preparations and the highest (OR 2.4) with the use of 50 µg or more EE.47 No studies have evaluated this risk related to low-dose EE combinations, and according to the adjacent progestogen compound.44 Conceivably, they might be similarly safe. Hypothetically, continuous delivery of hormones (eg, by a vaginal ring) might reduce the occurrence of auras and consequently lower the risk of stroke. There is, however, no scientific evidence to support this hypothesis.48

Although the evidence supporting the association of ischaemic stroke and EE is rather weak, most studies suggest an increased risk. Progestogen-only contraceptive pills containing NET might be considered safe due to their low dose. However, there are no studies concerning the therapeutic use of NET in which higher doses, such as 10 mg/day, are used. We suggest that the resulting circulating EE requires clinical consideration before prescribing NET to women with MwA for long-term use.

Higher risk for thromboembolic events

History or increased risk of VTE is an established contraindication to CHCs but not to progestogen-only contraception.18 Among HT users, the risk of VTE is higher in women using NET compared with women using MPA.20 However, the risk of thrombosis is seldom considered when prescribing therapeutic doses of progestogens, and to our knowledge, there are no studies evaluating the effects of therapeutic NET doses on VTE risk.

Nevertheless, due to the special characteristics of NET(A), we propose that the individual risk of thrombosis should be considered when prescribing NET(A) for therapeutic purposes. One group requiring special attention is obese women who are simultaneously at high risk for both endometrial hyperplasia and VTE. Among women at increased risk of thrombosis, alternative progestogens should be considered, and for example the levonorgestrel intrauterine system (LNG-IUS) could be a safe and highly effective option.49

Women at risk for breast cancer

In vitro and in vivo studies have demonstrated the stimulatory effect of NET on breast cancer cells.25 26 Also, in long-term follow-up the use of NET has resulted in a higher risk of breast cancer.27 Although there are no solid data, short-term use is likely to be safe, but for long-term use, alternative progestogens might offer a better alternative.