Volume 37, Issue 2 - SPECIAL ISSUE: Role Of Progestogens In Women’s Health: An Update / Editors: Adolf E. Schindler and René Druckmann

Background To analyze the allelic variants of genes of enzymes involved in estrogen metabolism: CYP1A1 , CYP1A2 , CYP19 and SULT1A1 using polymerase chain reaction-restriction fragment length polymorphism-restriction fragment length polymorphism (PCR-RFLP) analysis of women with histologically confirmed adenomyosis and women without proliferative diseases of pelvic organs was performed. We studied the following polymorphisms: CYP1A1 M1, T264 → C transition in the 3′-noncoding region; CYP1A2 * 1F , C734 → A transversion in CYP1A2 gene; C → T transition (Arg264Cys) in exon 7 of CYP19 ; SULT1A1 * 2 , G638 → A transition (Arg213His) in the SULT1A1 gene. Materials and methods The study included 804 patients. Group I (experimental group) consisted of 268 women with adenomyosis. Inclusion criteria were: histological verification of adenomyosis, consent of patients to participate in the study. Group II (control group) – 536 women without proliferative diseases of the uterus. Inclusion criteria were: lack of proliferative processes of the uterus histologically confirmed by ultrasound examination, patient’s consent to participate in the study. Results We found the significant association of C allele, T/C and C/C genotypes of the CYP1A1 gene (CYP1A1 M1 polymorphism), A allele, C/A and A/A genotypes of the CYP1A2 gene (CYP1A2 * 1F polymorphism) and the T allele, C/T and C/C genotypes of the CYP19 (Arg264Cys polymorphism) gene with the risk for adenomyosis. Conclusions Patients with adenomyosis had increased frequency of C allele, T/C and C/C genotypes of the CYP1A1 gene, A allele, C/A and A/A genotypes of the CYP1A2 gene and T allele and C/T and C/C genotypes of the CYP19 gene and, on the contrary, decreased frequency of the mutant allele and heterozygous and mutant homozygous genotype of the CYP1A2 gene compared to women without proliferative diseases of the uterus.

Combined hormonal contraception containing estrogen and progestogen and postmenopausal hormone therapy with estrogen ± progestogen are reported risk factors for venous thrombosis. The thrombotic risk varies by estrogen dose and type of progestogen. Estrogen combined with “newer generation” progestogens in combined oral contraceptives may have higher thrombotic risk than estrogen combined with older generation progestogens. Among postmenopausal women thrombotic risk also varies by type of hormone and mode of delivery. Although the risk of thrombosis with the different hormonal compounds is uncertain, it has definitely been attributed to the pharmacological effect of the hormones on hemostasis. Animal and cell culture studies have demonstrated the pharmacodynamics of progestogens with respect to hemostasis. Extrapolation from these studies to clinical conditions and further to clinical end points such as cardiovascular disease is, however, controversial. Few clinical studies have focused on the effect of progestogen only therapy on the hemostatic system in vivo. Most of the current knowledge regarding the in vivo effect of progestogens on hemostasis is obtained from studies with combined contraceptives. These results obviously reflect the combined influence of both estrogen and progestogen on hemostasis, and extrapolation to progestogen-only conditions is challenging. This paper discusses the pharmacodynamics of progestogens in relation to the hemostatic system, addressing results obtained in animal and cell culture studies and in clinical studies employing progestogen-only and combined oral contraceptives. The compiled results suggest that the major effect of progestogens on hemostasis is related to alterations in platelet function and the tissue factor pathway of coagulation. More studies focusing on these topics are warranted.

Transdermal estradiol (TE) application (using gels, patches or a novel spray) is now a preferred route of hormone therapy (HT) in menopausal women, because various risks such as venous thromboembolism, stroke and unwanted hepatic effects can be reduced compared with oral HT. However, in the presence of an intact uterus, concurrent administration of progestogen is needed for endometrial protection. Due to the variety of progestogens available and differences in their clinical effects, the selection of the most appropriate substance and dosing for individual combination therapy can be difficult. This is especially true for TE gels and the novel spray because no fixed combination products are commercially available, meaning all progestogens must be added separately, and even for patches only two transdermal synthetic progestogens are available. The aim of this review was to summarize data on the endometrial effects of the different progestogens and to provide practical recommendations for the choice of progestogen (type and dosing), with a focus on endometrial protection when using TE, especially when using the novel estradiol (E2) spray.

As an estrogen-dependent disease, endometriosis was thought to become less active or regress with the onset of the menopause. However, based on some new data, we are discovering that this pathology can emerge or reappear at this period of life. Clinicians must consider it as a possible cause for cases of pelvic pain, and heavy bleeding. Authors have described a possibility of transformation of the intraperitoneal proliferation into a malignant type with ovarian, bowel and even lung metastasis. The risk of transformation into an ovarian cancer is around 2 or 3%. The role of menopausal hormonal therapy will be discussed as in recurrence in the case of residue existence, especially after incomplete surgery. Is it possible to prescribe hormonal therapy to a menopausal women suffering climacteric symptoms as it could trigger a recurrence of endometriosis and even an increased risk of malignant degeneration? This remains unclear. It is an unresolved therapeutic dilemma; the choice between surgery or medical treatment?