European Progestin Club Guidelines for prevention and treatment of threatened or recurrent (habitual) miscarriage with progestogens.

This guideline has been developed based on studied and clinical investigations. Therefore, it appears to be appropriate to use all the available evidence, which are very encouraging, in a summarized form to propose guidelines by a group of European experts in order to give the gynecologists, obstetricians and reproductive medicine specialists have direction with regard to the prevention or treatment of miscarriage for the benefit of the endangered pregnancies. There are a number of statements, opinions and guidelines already published for this topic, which are not entirely in agreement.

Endometriosis at all ages: diagnostic ultrasound.

Endometriosis is a gynecological disease affecting about 10% of the female population. The multifactorial hormonal, inflammatory, genetic, mental and behavior pathogenesis can result in chronic pelvic pain, blooding disorders and infertility causing disruption of quality of life. Correct diagnosis of the extension and topography is substantial in defining the adequate therapeutic strategy. In an increasing proportion of the cases, endometriosis is being managed medically and para-medically; diagnostic or therapeutic surgery can often be avoided or delayed. Transvaginal sonography is considered being the first-line imaging method in the diagnosis of pelvic endometriosis. The paradigm shift from the belief that endometriosis only affects women of reproductive age has drawn attention to endometriosis in both premenarchal and postmenopausal patients. This review resumes the actually recommended ultrasound signs in the case of patients in menstrual age. Specific diagnostic approaches in adolescent and menopausal patients are highlighted.

Female urine incontinence: vaginal erbium laser (VEL) effectiveness and safety.

Urinary incontinence is a common health problem that impacts the quality of life of women at different ages. Its physiopathology is not unequivocal, and it is necessary to consider the stress urinary incontinence (SUI), the overactive bladder syndrome and the mixed incontinence (MUI). According to the type of incontinence, its impact on the quality of life and age of the patients, therapeutic strategies are currently summarized in physiotherapy, surgery and drug treatments. We already know the benefit/risk ratio of each of these strategies. Our objective is to evaluate the potential effectiveness and safety of the VEL, an innovative vaginal laser technique (VEL - Vaginal Erbium Laser, erbium yttrium-aluminum-garnet -Er: YAG) a non-invasive laser proposed as a treatment for SUI, overactive bladder syndrome and MUI. The mechanisms of action of lasers are discussed in general and those of VEL in particular with the description of the Smooth® mode. To do this, we have collected the 21 published studies including the first randomized vs. placebo and two pilot studies of intra-urethral VEL. In conclusion: VEL procedures already have their place between the rehabilitation of the perineal floor and surgery. Further properly sized, randomized studies are needed to evaluate the laser treatments in comparison with other therapies, as well as to assess the duration of the therapeutic effects and the safety of repeated applications.

Ultrasound screening of ovarian cancer.

Ovarian cancer has a high mortality rate. The most common serous type spreads rapidly throughout the peritoneal cavity when 5-year survival is 10%. If diagnosed in earlier stages where the cancer is still confined to the ovary, this survival rate is about 90%. This is the reason to be interested in screening at earlier stages in the average-risk general population. Thus, annual transvaginal ultrasound (TVS) alone or as a multimodal screening test following serum carbohydrate antigen 125 (CA125) has been investigated. Ultrasound lacks sensitivity and specificity; new contrast-enhanced approaches might improve these. When the serum marker is combined with ultrasound and interpreted by a rise in the level rather than by a fixed cut-off, improved sensitivity and specificity and a late but not significant reduction in mortality are observed. Further investigations could highlight the interest of a shorter than annual screening, of a long-term follow-up and new contrast-enhanced ultrasound techniques.

Genitourinary syndrome of menopause (GSM) and laser VEL: a review.

The purpose of this publication is to summarize the results of the vaginal erbium:yttrium-aluminum-garnet (Er:YAG) Smooth® laser (VEL) on the vaginal atrophy component of the genitourinary syndrome of menopause (GSM). GSM has two categories of clinical signs related to estrogen deficiency: symptoms of vulvovaginal atrophy (VVA) and urinary symptoms. This symptomatology is chronic, progressive over the years and affects a majority of women concerned by natural menopause but not exclusively: we must also consider the growing number of survivors of gynecological or non-gynecological cancers (breast, cervix, uterus, vagina, anus, etc.). At a time when hormonal treatment of menopause is contested as is the installation of under urethra prosthesis, the innovation provided by the VEL technology has the merit of offering the women concerned an effective therapeutic alternative with the security of a patent. The VEL technology has an original and unique process: acting only by thermal effect and not by ablation on tissue, VEL is a safe solution in terms of side effects and potential complications. Studies have been increasing since 2012 and all demonstrate a significant improvement in the GSM signs and symptoms, as well as an improved sexual life after VEL treatment. Double-blind, placebo-controlled, randomized studies are expected in order to ultimately confirm the safety and effectiveness of VEL.

Classification and pharmacology of progestins.

Besides the natural progestin, progesterone, there are different classes of progestins, such as retroprogesterone (i.e. dydrogesterone), progesterone derivatives (i.e. medrogestone) 17alpha-hydroxyprogesterone derivatives (i.e. chlormadinone acetate, cyproterone acetate, medroxyprogesterone acetate, megestrol acetate), 19-norprogesterone derivatives (i.e. nomegestrol, promegestone, trimegestone, nesterone), 19-nortestosterone derivatives norethisterone (NET), lynestrenol, levonorgestrel, desogestrel, gestodene, norgestimate, dienogest) and spironolactone derivatives (i.e. drospirenone). Some of the synthetic progestins are prodrugs, which need to be metabolized to become active compounds. Besides the progestogenic effect, which is in common for all progestins, there is a wide range of biological effects, which are different for the various progestins and have to be taken into account, when medical treatment is considered.

Long-term use of progestogens--getting the balance right: molecular biology and the endometrium.

The role of progestins in long-term treatment has recently been under scrutiny, in particular as their effects on organs other than the endometrium, such as the breast or the cardiovascular system, could give rise to undesirable reactions. The use of progestins in hormone replacement therapy has highlighted the importance of choice of progestin. Insights into the molecular biology of normal processes in the endometrium can help to find accurate markers for progestin effects and help select progestins with a better benefit-risk profile. Such insight can also lead to a better understanding of the etiology of menstrual and fertility disorders and ultimately to new therapeutic approaches.

Progesterone and the immunology of pregnancy.

The foetal-placental unit is a semi-allograft and the immunological recognition of pregnancy, together with the subsequent response of the maternal immune system, is necessary for a successful pregnancy. This recognition of pregnancy results in an upregulation of progesterone receptors on activated lymphocytes amongst placental cells and decidual CD56+ cells. In the presence of sufficient progesterone, these cells synthesise progesterone induced blocking factor (PIBF), a mediator that exerts substantial anti-abortive activities. PIBF affects B cells and induces an increased production of asymmetric, non-cytotoxic antibodies. It also alters the profile of cytokine secretion by activated lymphocytes resulting in an increase in the production of non-inflammatory, non-cytotoxic interleukins (IL) (e.g. IL-3, IL-4 and IL-10) and a reduction in the production of inflammatory, cytotoxic cytokines (e.g. interferon (IFN)-delta, tumour necrosis factor (TNF)-alpha and IL-2). PIBF also inhibits the cytotoxicity of natural killer (NK) cells by blocking their degranulation and perforin release, as well as inhibiting IFN-delta, TNF-alpha and IL-2-mediated transformation of NK cells into detrimental lymphokine activated killer (LAK) cells.

Does purified Swedish pollen extract, a nonhormonal treatment for vasomotor symptoms, inhibit the CYP2D6 enzyme system?

OBJECTIVE: Tamoxifen, used for treatment and chemoprevention of breast cancer, is converted to 4-hydroxy-tamoxifen and other metabolites by cytochrome P450 (CYP) enzymes. It can often initiate or exacerbate vasomotor symptoms (VMS). Selective serotonin reuptake inhibitors (SSRIs) have been prescribed for VMS in such participants in which estrogens are contraindicated. However, SSRIs are strong CYP2D6 inhibitors and can reduce the efficacy of tamoxifen. A nonhormonal purified Swedish pollen extract (Relizen is also prescribed in other countries under different registered trade names: Sérélys, Femal, Femalen), has shown efficacy versus placebo in treating VMS in a randomized, double-blind controlled trial. The objective of this study was to evaluate the in vitro effects of purified Swedish pollen extract on the CYP2D6 enzyme. METHODS: PE-F/S, the powder form of purified Swedish pollen extract, contains 75% pollen/pistil extract P182 and 25% pollen extract GCFem. It was tested for its potential to inhibit the human CYP isoenzyme, CYP2D6, in pooled human liver microsomes. Quinidine, a known inhibitor of CYP2D6, was used as a reference. Concentrations of purified Swedish pollen extract ranged from 1.65 to 400 µg/mL, approximately five times the recommended daily dose for VMS. RESULTS: Inhibition of CYP2D6 with purified Swedish pollen extract was negligible at all concentrations and ranged from -6.53% to 10.67%. Inhibition of CYP2D6 enzyme with Quinidine increased in a linear dose-related fashion from -7.07% at 2.06  nM to 84.05% at 500  nM. CONCLUSIONS: Purified Swedish pollen extract is a nonhormonal treatment of VMS that does not show inhibition of the CYP2D6 enzyme. This may have important clinical utility for women using tamoxifen for breast cancer treatment or chemoprevention who experience VMS.

Progestins and their effects on the breast.

Nowadays, when the available scientific data on the in vivo effects of progestins on mammary gland tissue remain controversial, it is of utmost importance to establish adequate criteria to evaluate their actions. One of the reasons for this situation is that a variety of progestins have been studied using a number of different study designs. In addition, data relating to the effects of progestins on breast tissue have been interpreted differently from country to country. Recent data indicate that some progestins clearly oppose the favourable effects of estrogens on a number of important metabolic processes, e.g. influencing insulin-like-growth-factor (IGF)-1 serum levels. IGF-1 is a mitogenic and antiapoptotic peptide involved in growth regulation of breast epithelial cells. Circulating IGF-1 exerts endocrine action, it regulates growth hormone secretion by a negative feedback mechanism. In the past few years, both laboratory investigations and epidemiologic studies provided strong evidence that the IGF-1/growth hormone axis is involved in human cancer risk [Maturitas 29 (1998) 61; Horm. Res. 51 (1999) 34; Eur. J. Cancer 36 (2000) 1224; Maturitas 41 (2002) 299] Some progestins also have effects on the enzymes in breast tissue that are responsible for the local synthesis of estradiol. Thus, whilst progestins without androgenic action have been found to markedly inhibit these enzymes, an equivalent degree of inhibition is not achieved with testosterone-derivatives. Therefore, special attention should be paid to the various partial actions of the different progestins and their effects on breast tissue. Furthermore, factors such as the duration of breast tissue exposure to progestin activity, the influence of different regimens on protective apoptotic mechanisms in the breasts, as well as dose levels and the degree of mammary gland tissue differentiation throughout treatment, should also be considered.

Classification and pharmacology of progestins.

Besides the natural progestin, progesterone, there are different classes of progestins, such as retroprogesterone (i.e. dydrogesterone), progesterone derivatives (i.e. medrogestone) 17alpha-hydroxyprogesterone derivatives (i.e. chlormadinone acetate, cyproterone acetate, medroxyprogesterone acetate, megestrol acetate), 19-norprogesterone derivatives (i.e. nomegestrol, promegestone, trimegestone, nesterone), 19-nortestosterone derivatives norethisterone (NET), lynestrenol, levonorgestrel, desogestrel, gestodene, norgestimate, dienogest) and spironolactone derivatives (i.e. drospirenone). Some of the synthetic progestins are prodrugs, which need to be metabolized to become active compounds. Besides the progestogenic effect, which is in common for all progestins, there is a wide range of biological effects, which are different for the various progestins and have to be taken into account, when medical treatment is considered.

Dysfunctional uterine bleeding: from adolescence to menopause.

Dysfunctional uterine bleeding (DUB) is defined as excessive or prolonged uterine bleeding in premenopausal women that is not caused by pelvic pathology, medications, systemic disease or pregnancy. It is a common condition that can lead not only to physical symptoms such as iron deficiency, anaemia, cramps and fatigue, but also has significant psychological and social effects that impair a woman's quality of life. Progesterone is highly important in the regulation of menstrual bleeding and a progesterone-deficient anovulatory state is a common cause of DUB. There are a wide range of treatment options available including hormonal therapies (oral cyclical progestogens, depot progestogens, progestogen-releasing intrauterine devices, combined oral contraceptives, danazol, gonadotrophin-releasing hormone analogues and hormone replacement therapy), non-hormonal therapies (non-steroidal anti-inflammatory drugs and antifibrinolytic drugs) and surgery (hysterectomy and endometrial ablation). The choice of appropriate therapy should be based on factors such as the mechanism behind the DUB, which symptoms are most problematic, and the woman's need for fertility or contraception. However, there is currently a lack of clinical evidence to help support these decisions.

Profile of the progesterone derivative chlormadinone acetate - pharmocodynamic properties and therapeutic applications.

Chlormadinone acetate (CMA) is a derivative of progesterone (17alpha-acetoxy-6-chloro-4,6-pregnadiene-3,20-dione), first synthesized in 1961 and is used as an orally effective progestogen in hormone replacement therapy (HRT), and in combination with ethinyl estradiol (EE) in contraception since 1999. Chlormadinone acetate has a strong progestogenic effect - about one-third higher than that of progesterone - and may vary depending on the previous effect of an estrogen, i.e., estrogens may promote the formation of progesterone receptors and proliferation of the endometrium. Like progesterone, it is anti-estrogenic and has no partial androgenic effect (at the doses used for contraception and HRT). In contrast to progesterone, it has a slight glucocorticoid effect, a pronounced anti-androgenic effect and no anti-mineralocorticoid effect. No pregnancy-maintaining effect of CMA has been demonstrated in humans. The anti-androgenic effect of CMA is presumed to be the result of both its binding to androgen receptors - competitively inhibiting the effect of endogenous testosterone and dihydrotestosterone - and the competitive inhibition of 5alpha-reductase. In this respect, dosing of CMA is crucial; agonistic effects are observed when doses are increased from those optimal for an antagonistic effect. Chlormadinone acetate has a strong anti-gonadotropic effect, through negative feedback on gonadotropin secretion, and has been used for more than 20 years alone for contraception in arterial risk patients. The clinical and metabolic tolerability of CMA has been demonstrated in numerous clinical studies with duration of treatment of up to 2.5 years. The more recent application of CMA as an oral contraceptive in combination with EE (Neo Eunomin, Belara) has proven highly successful, with studies reporting excellent contraceptive efficacy, high tolerability and adherence due to a good side effect profile and positive effects on preexisting dysmenorrhea, skin and hair conditions.