Volume 37, Issue 1 - SPECIAL ISSUE: Role Of Progestogens In Women’s Health: An Update / Editors: Adolf E. Schindler and René Druckmann

Background Severe forms of adenomyosis are a serious gynecological problem. In most cases, conservative treatment of this pathology is unsuccessful. Adenomyomectomy by Osada’s approach seems to be the most promising solution. The present study evaluated the follow-up results of this type of surgery in patients with adenomyosis and infertility. Materials and methods The prospective study included 26 patients with severe forms of adenomyosis who underwent an adenomyomectomy using Osada’s approach. In 18 patients (69%), infertility was the main indication for surgical treatment. The follow-up period lasted from July 2012 to January 2018. Results The median post-operative follow-up period was 18 months. For the first 12 months patients received hormonal therapy. In all postoperative patients, the menstrual cycle had normalized, and other symptoms of the disease had disappeared. Seven patients continue to receive postoperative hormonal treatment. Three individuals got spontaneously pregnant; two of them delivered full-term babies by cesarean section. Six patients are planning a pregnancy with assisted reproductive technology. Conclusion In the present study, the organ-preserving surgery of severe adenomyosis performed using Osada’s method appeared to be a good alternative to hysterectomy. It stopped the development of pathological symptoms of the disease and restored the patient’s reproductive function.

The contraceptive pill is an effective and very safe method to control pregnancies. It was developed 60 years ago, and despite that the composition has been the same since it was first developed (estrogen and progestogen), over the years the concentration of ethinyl estradiol has been reduced to improve tolerability. Nevertheless, progestogens are the basic active agent of hormonal contraception. The mechanism of progestogens is a multimodal one and basically three modes of contraceptive action can be distinguished: (a) A strong antigonadotrophic action leading to the inhibition of ovulation. The necessary dosage of ovulation inhibition per day is a fixed dosage that is intrinsic to each progestogen and independent of the dosage of estrogen used or the partial activities of the progestogen or the mode of application. (b) Thickening of the cervical mucus to inhibit sperm penetration and (c) desynchronization of the endometrial changes necessary for implantation. The on the market available progestogens used for contraception are either used in combined hormonal contraceptives (in tablets, patches or vaginal rings) or as progestogen only contraceptives. Progestogen only contraceptives are available as daily oral preparations, monthly injections, implants (2–3 years) and intrauterine systems (IUS). Even the long-acting progestogens are highly effective in typical use and have a very low risk profile. According to their introduction into the market, progestogens in combined hormonal contraceptives, have been described as 1st, 2nd, 3rd and 4th generation progestogens. The different structures of progestogens are derivatives from testosterone, progesterone and spironolactone. These differences in the molecular structure determine pharmacodynamic and pharmacokinetic differential effects which contribute to the tolerability and additional beneficial or therapeutic effects whether used in combined oral contraceptive (COC) or as progestogen only drugs. These differences enhance the individual options for different patient profiles. The new development of polymers for vaginal rings allowed on the one hand, the improvement of the estrogen/progestogen combination in these rings especially regarding the comfort of use for women (e.g. avoiding the use of cold chains or packages with up to 6-month rings) and on the other hand, the development of progestogen only formulations. Another future development will be the introduction of new progestogen only pills that will provide effective contraceptive protection with more favorable bleeding patterns and a maintenance of ovulation inhibition after scheduled 24-h delays in pill intake than the existing progestogen only pill (POP) with desogestrel (DES).

Allopregnanolone (ALLO) has a crucial role in brain development and remodeling. Reproductive transitions associated with endocrine changes affect synthesis and activity of ALLO with behavioral/affective consequences. Pregnancy is characterized by an increased synthesis of progesterone/ALLO by the placenta, maternal and fetal brains. This suggests the critical role of these steroids in maternal brain adaptation during pregnancy and the development of the fetal brain. ALLO is brain protective during complications of pregnancy, such as preterm delivery or intrauterine growth restriction (IUGR), reducing the impact of hypoxia, and excitotoxic brain damage. Negative behavioral consequences of altered progesterone/ALLO maternal brain adaptation have been also hypothesized in the post-partum and targeting ALLO is a promising treatment. Hormonal contraception may alter ALLO action, although the effects are mostly related to a specific class of progestins. Understanding the interactions between ALLO and the endocrine environment is crucial for more effective and tailored hormonal treatments.

Doctors and patients fear the risk of breast cancer when using hormone replacement therapy (HRT). This review focuses on the choice of progestogen for HRT in menopausal. The Women’s Health Initiative (WHI) has been the only large double-blind placebo-controlled study testing the risk of breast cancer (BC) using HRT. No increased risk using estrogen (E)-only was seen, there was a significant decrease in mortality due to BC after the use of HRT which persisted during the recent 18-year follow-up of the WHI. In contrast in the combined arm the risk increased. In about 20 observational studies using mostly medroxyprogesterone acetate (MPA) or estradiol-norethisterone acetate (NETA) an increased BC-risk was observed comparable with the WHI. Only for natural progestogen, progesterone and for dydrogesterone (retro-isomer of progesterone) was no increased risk seen for up to 5–8 years, when compared directly with other progestogens, but for longer treatment an increased risk cannot be excluded. In contrast, the mortality due to BC after use of E-only and combined HRT decreased in about a dozen observational studies, and was very recently confirmed in a Finnish study evaluating 490,000 women using estradiol (E2) plus different progestogens. There have been already more than 70 studies evaluating the risk of BC during HRT, and still there are many open questions. Therefore, this review covers our own and other experimental research which could answer important questions. Experimental research has demonstrated that certain synthetic progestogens, but not progesterone and to some extent also not dydrogesterone, can accelerate the proliferation of breast cancer cells in vitro and in animal studies via special cell membrane components which we recently also detected in patients with BC, and we found differences comparing all available synthetic progestogens. Derived from these mechanisms future research may provide screening for patients at risk and predict the prognosis of possible BC.