Progestogen Preparations Research Articles

Non-inferiority study to compare the efficacy of relugolix with dienogest for endometriosis-associated pain and usefulness of administering relugolix prior to dienogest (READY study): study protocol for a multicenter randomized controlled study

BackgroundEndometriosis presents as endometrial tissue growths outside the uterine cavity with its major symptoms including dysmenorrhea and infertility. Progestin preparations, such as dienogest, are the first-line therapy for endometriosis symptoms, but may cause abnormal uterine bleeding. A gonadotropin-releasing hormone (GnRH) agonist may also be used to ease symptoms, but may induce flare-ups. Relugolix is a non-peptide GnRH antagonist that does not induce flare-ups. This study aims to compare the efficacy of relugolix with that of dienogest for reducing endometriosis-associated pain, and to evaluate if relugolix, administered prior to dienogest, decreases abnormal uterine bleeding.MethodsA multicenter, open-label, active-controlled, non-inferiority randomized study will be conducted at 11 sites in Japan. A total of 100 premenopausal patients aged ≥ 18 years with endometriosis, a maximum visual analog scale (VAS) score > 30 for endometriosis-associated pain, and dysmenorrhea or pelvic pain of at least moderate severity on the Biberoglu & Behrman (B&B) scale will be randomized in a 1:1 ratio to either a relugolix group or dienogest group. Patients in the relugolix group will receive 40 mg oral relugolix once daily for 16 weeks, followed by 1 mg oral dienogest twice daily for 24 weeks. Patients in the dienogest group will receive oral dienogest 1 mg twice daily for 24 weeks. The primary outcome will be change in maximum VAS score for endometriosis-associated pain from baseline to 13–16 weeks after start of treatment. The secondary outcomes will include VAS score for dyspareunia, B&B score for dysmenorrhea, severity of induration in the pouch of Douglas, restricted uterine mobility, pelvic tenderness, quality of life, analgesic use, and ovarian endometrioma diameter. The safety outcomes will include treatment-emergent adverse events, bone density, bone markers, menstrual status, genital bleeding, and endometrial thickness.DiscussionThis study will determine the efficacy of relugolix for improving endometriosis-associated pain and dienogest-induced abnormal uterine bleeding. The results will support treatment decisions regarding endometriosis-associated pain, and the introduction of new treatments to reduce dienogest-induced abnormal uterine bleeding.Trial registrationJapan Registry of Clinical Trials ID jRCTs061230064. Registered on 29 September 2023.

Availability, Usage, and Preferences of Estradiol and Progestogen Preparations for Puberty Induction from a Multicentral Perspective

Introduction: Natural oestrogen administration as oral or transdermal 17β-estradiol is recommended for pubertal induction in girls with hypogonadism. However, suitable low-dose formulations are not consistently available globally. This questionnaire study aimed to identify the current availability of oestrogen and progesterone preparations worldwide. Methods: Endorsed by the ESPE Turner Syndrome Working Group, the questionnaire targeted paediatric endocrinologists. Questions focused on accessibility of oral/transdermal 17β-estradiol and progestogen preparations. Responses were collected through a SurveyMonkey survey disseminated via ESPE channels, direct outreach, and conferences from June 2020 to December 2022. Results: Participation included 229 healthcare professionals from 45 countries. Oral and transdermal 17β-estradiol in adult dosage was highly accessible (86.5% and 84.3%), with transdermal administration the preferred form (62.8%). Most commonly available estradiol preparations included 50 μg patches (32 countries) and 1 or 2 mg tablets (65.8% and 71.1% countries). However, 0.5 mg 17β-estradiol tablets were available in only 20% of respondents from 8 countries. Patches delivering 14 or 25 μg/day of 17β-estradiol were available in 3 and 20 countries, respectively. Oral progestogen had widespread availability (96.0%) and preference (87.0%), while transdermal usage was limited to 15.2% of respondents. Conclusion: This study highlights global challenges in accessing suitable hormone preparations for female pubertal induction. In most countries, the lowest dose of the estradiol is 50 µg for patches and 2 mg for tablets. Appropriate low-dose 17β-estradiol tablets are much less available than low-dose patches. Our survey underscores the importance of adapting guidelines to local availability, and the need for improved accessibility to address these global disparities.

Gonadotropin-Releasing Hormone (GnRH)/GnRH Receptors and Their Role in the Treatment of Endometriosis.

Endometriosis, defined as the development of endometrial tissue outside of the uterine cavity, is a common gynecological disorder. The prevalence of pelvic endometriosis approaches 6%-10% in the general female population, and in women with pain, infertility, or both, the frequency is 35%-50%. The gold standard recommended process for diagnosing endometriosis is laparoscopy, an invasive surgical procedure, with or without histologic verification. The currently available nonsurgical treatments include oral contraceptives (estrogen-progestogen preparations), progestogen preparations (containing progesterone derivatives), androgenic hormones (danazol), and gonadotropin-releasing hormone (GnRH) agonists and antagonists. Two GnRH types have been discovered in mammals, GnRH I and GnRH II. In particular, GnRH I is released by the hypothalamus; however, it can be present in various tissues and organs of the body, including neural tissue, where it exerts neuroendocrine, autocrine, and paracrine actions in the peripheral and central nervous system (CNS). Interestingly, another GnRH isoform, GnRH III, has been identified, which has 60% similarity with GnRH I from which it varies by four amino acids. This peptide has been shown to have a significant role in reproduction, specifically in gametogenesis and steroidogenesis. Further research is needed to identify innovative treatment options for endometriosis, such as the therapeutic exogenous administration of GnRH II or antagonists of the GnRH I receptor. In this review, we examined the role of GnRH in endometriosis, outlining the specific actions of GnRH and GnRH receptors (GnRHRs). The innovative use of GnRH analogs and antagonists in the treatment of endometriosis is also discussed.

Relationship of Mom Knowledge about Contraceptive Pills and Compliance the Use of Contraceptive Pills in Medan Tuntungan

Knowledge is the result of "knowing" and this occurs after people have sensed a certain object. Sensing of objects occurs through the five human senses, namely sight, hearing, smell, taste and touch by themselves. The composition of the contraceptive pill contains synthetic estrogen and progestin preparations so that pregnancy can be prevented by suppressing ovulation where the hormones LH and FSH are suppressed, thickening cervical mucus, and preventing thickening of the endometrium. The prevalence of family planning according to family planning devices from active family planning participants in Indonesia is 66.20%. The dominant contraceptive methods are injections (34%) and birth control pills (17%). This study aims to determine the relationship between knowledge of women of childbearing age about birth control pills with adherence to the use of birth control pills. The research methodology in this study used analytical observation with a cross sectional approach, 40 samples by purposive sampling, in Baru Ladang Bambu, Medan Tuntungan. Based on the results of statistical analysis obtained by 40 respondents, it can be concluded that there is a relationship between the knowledge of women of childbearing age about birth control pills with adherence to the use of birth control pills, which means that the better the knowledge of women of reproductive age couples, the more obedient in the use of birth control pills.

Hormonal Contraception: Systemic Estrogen and Progestin Preparations.

Combined hormonal contraception (CHC) are short-acting, reversible methods containing both estrogen and progestin. Available CHC methods include combined oral contraceptives, transdermal patches, and vaginal rings. The combined oral contraceptive remains the most commonly used contraceptive method in the United States. The general principles of CHC will be reviewed, including mechanism of action and effectiveness. Unless otherwise stated, these principles apply to all CHCs. When discussing clinical studies and specific considerations related only to pills, patches, or rings, the method(s) will be specified. Words that specify sex are used when discussing studies in which sex was specified.

Систематический анализ экспериментальной и клинической фармакологии препаратов микронизированного прогестерона

Micronization of progesterone is necessary for improving the pharmacokinetic properties of progestin preparations that increase the chances of favorable pregnancy outcomes and are essential for hormone replacement therapy. A computer analysis of 637 publications on micronized progesterone (MP) made it possible to systematize the results of studies (1) on the pharmacokinetics of MP preparations, (2) the use of MP in therapy for hot flashes, (3) the effect of MP on the central nervous system, (4) the normolipidemic properties of MP, (5) the use of MP to maintain pregnancy and (6) to improve the efficiency of reproductive technologies. Key words: safety issues, micronized progesterone, pregnancy maintenance, Prajisan, pharmacoanalytics

Management of Premenstrual Syndrome: Green-top Guideline No. 48.

Management of Premenstrual Syndrome: Green-top Guideline No. 48.

Comparative evaluation progestin preparations of the effect graviditas transformation of endometrial undeveloping pregnancy of the I trimester

The results of histological and immunohistochemical studies of the endometrium graviditas during non-developing pregnancy of the first trimester showed that the defective decidualization of the endometrium and poorly formed tangles of the spiral arteries are significantly more common in case of treatment with micronized progesterone than in case of treatment with dydrogesterone. The irregular distribution and increased expression of estrogen receptors in the glands and stroma of the endometrium are indicators of pathology of the first phase of the menstrual cycle.

Health Outcomes as Drivers of Trends in Hormone Therapy Use

The use of combined estrogen–progestin therapy has varied greatly during the past few decades. Researchers evaluated U.S. trends in hormone therapy (HT) use by user age and calendar year between 1970 and 2010. Data from the National Health and Nutrition Examination Survey and the National Prescription Audit were combined in an analysis targeting use of noncontraceptive estrogen–progestin preparations of HT. Before 1980, prevalence …

PIH25 - Pharmacoeconomic Analysis of Progestogen Preparations for Threatened Abortion Treatment in Ukraine

PIH25 - Pharmacoeconomic Analysis of Progestogen Preparations for Threatened Abortion Treatment in Ukraine

Progestin therapy for endometrial cancer: The potential of fourth-generation progestin (Review)

Progestin preparations are made of synthetic progesterone and have often been used for hormone therapy in gynecological patients with endometriosis or endometrial cancer. Hormone therapy using progestin is considered to be one of the effective means of treatment particularly when dealing with endometrial cancer (an estrogen-dependent tumor). Numerous reports have been published concerning its efficacy in advanced or recurrent cases of atypical endometrial hyperplasia or endometrial cancer. Dienogest has been developed as a fourth-generation progestin for hormone therapy for endometriosis that can be used with high safety for long periods of time. In Japan, dienogest has been recommended as a first-line drug for endometriosis-associated pain. However, its antitumor activity has also been attracting close attention following a report that this drug suppressed the proliferation in vitro of endometrial cancer-derived cell lines which failed to respond to other progestins such as medroxyprogesterine acetate (MPA). The mechanism for antitumor activity of dienogest is considered to differ from the mechanism for antitumor activity of conventional progestin preparations used for treatment of endometrial cancer. This drug is expected to be clinically applicable as a new drug for the treatment of endometrial cancer.

Breast cancer incidence trends in Norway—explained by hormone therapy or mammographic screening?

A decline in breast cancer incidence has been observed in several countries after 2002. Reduced use of menopausal hormonal therapy (HT), as a consequence of the publication of results from the Women's Health Initiative, has been argued to be the main reason. In Norway, the governmentally funded Norwegian Breast Cancer Screening Program (NBCSP) was implemented during the same time period as the increased use of HT. This study investigated trends in breast cancer incidence by use of HT and introduction of the screening program. We obtained rates of breast cancer from the Cancer Registry of Norway and sales data of HT preparations from the Norwegian Institute of Public Health. Mammography rates were estimated from published reports. Breast cancer incidence rates increased steadily from 1956 to the end of the 20th century, particularly in women aged 55-69 during 1996-2002 residing in the counties where the NBCSP was first introduced. The rates declined after 2002-2003. HT use increased in 1987-2001, peaking around year 2000. In particular, sales of combined estrogen and progestogen preparations declined after 2002. Among women aged 55-59, rates of hormone receptor positive breast cancers peaked in 2000-2003. No such trend was seen in other age groups. In conclusion, the interpretation of breast cancer incidence trends in Norway from 1987 to 2009 is complicated because the NBCSP was introduced during a period with increasing HT use. Both factors likely contributed to the observed trends, and the role of each may vary across age groups.

Hormonal contraception--what kind, when, and for whom?

In Germany today, one-third of the 20 million women of child-bearing age use combined oral contraceptives (COCs). In this article, we summarize the current knowledge of the mode of action, wanted and unwanted side effects, and long-term risks of COCs. The levonorgestrel intrauterine device (IUD) and long-acting injectable or implantable monophasic progestogen preparations offer comparable contraceptive efficacy to COCs. Nonetheless, they are less frequently used in Germany than COCs, because of their propensity to cause breakthrough bleeding. Selective review of the literature. COCs suppress gonadotropin secretion and thereby inhibit follicular maturation and ovulation. Their correct use is associated with 0.3 pregnancies per 100 women per year, their typical use, with 1 pregnancy per 100 women per year (Pearl index). COCs have effects on the cardiovascular and hemostatic systems as well as on lipid and carbohydrate metabolism. When given in the presence of specific risk factors, they significantly increase the likelihood of cardiovascular disease and thromboembolism. Women with persistent human papilloma virus (HPV) infection who take COCs are at increased risk of developing invasive cervical cancer. On the other hand, COCs lower the cumulative incidence of endometrial and ovarian cancer by 30% to 50%, and that of colorectal cancer by 20% to 30%. Other malignancies seem to be unaffected by COC use. As long as personal and familial risk factors are carefully considered, COCs constitute a safe, reversible, and well-tolerated method of contraception.

Menopausal hormone therapy and risk of ovarian cancer in the European prospective investigation into cancer and nutrition

The association between menopausal hormone therapy (HT) and risk of ovarian cancer was assessed among 126,920 post-menopausal women recruited into the European Prospective Investigation into Cancer and Nutrition. After an average of 9-year follow-up, 424 incident ovarian cancers were diagnosed. Cox models adjusted for body mass index, smoking status, unilateral ovariectomy, simple hysterectomy, age at menarche, number of full-term pregnancies, and duration of oral contraceptives were used. Compared with baseline never use, current use of any HT was positively associated with risk (HR [hazard ratio], 1.29; 95% CI [confidence interval], 1.01-1.65), while former use was not (HR, 0.96; 95% CI, 0.70-1.30). Current estrogen-only HT was associated with a 63% higher risk (HR, 1.63; 95% CI, 1.08-2.47), while current estrogen plus progestin was associated with a smaller and non-significant higher risk (HR, 1.20; 95% CI, 0.89-1.62). Use of tibolone was associated with a twofold greater risk (HR, 2.19; 95% CI, 1.06-4.50), but was based on small numbers. In conclusion, women who currently use HT have a moderate increased risk of ovarian cancer, and which may be stronger for estrogen-only than estrogen plus progestin preparations.

Postmenopausal hormone therapy and cognition: effects of timing and treatment type

Setting Hormone therapy used for the management of postmenopausal symptoms in older women appears to result in variable effects on cognitive function, depending on study design, subjects, tests used, and types of therapy.Objective To determine the effects of estrogen-only and estrogen plus progestogen preparations on cognitive performance (cognitive status, general and working memory) when taken ‘early’ and ‘late’ from the onset of menopause.Method The study consisted of 410 women who were participants in a longitudinal study, first recruited at age 40–80 years. They were tested for change over 5 years as an observational cohort by the Mini-Mental State Examination, National Adult Reading Test and the Wechsler Memory Scale Version 3. Cognitive decline, measured by age-adjusted scores, was defined as ≥10% negative change in each individual woman.Results Controlling for age and lifestyle factors, and using the criterion of decrease in score ≥10% over 5 years for ‘cognitive decline’, ‘early start’ of hormone therapy (<3 years from menopause) was strongly associated with reduction in risk by the Mini-Mental State Examination (estrogen-only preparation, p = 0.005) but with increase in risk for general memory (with estrogen plus progestogen preparation, p = 0.02). Overall, there were no major effects on subgroups with type/timing of hormone therapy in relation to testing for a negative change in cognitive function.Conclusion ‘Early start’ of estrogen-only hormone therapy was associated with reduced risk of global cognitive decline, and ‘early start’ estrogen-only and estrogen/progestogen hormone therapies showed increased risks of general memory decline. Even though this study did not have the power to discriminate between minor and mixed effects, it suggests that cognitive effects of hormone therapies may be mixed, depending on cognitive domain and timing of use/type of preparation.

The influence of oral contraceptives on lipoprotein status (author's transl)

Sera from 500 female blood donors, aged 18-40 years, were examined by quantitative lipoprotein electrophoresis. 218 women had been taking oral contraceptives for more than 3 months; the remaining 282 not on contraceptives acted as controls. The two groups were similar as to age distribution, weight and smoking habits. There were five sub-groups according to the composition of the contraceptives. It was found that all contraceptives had a favourable influence on the atherogenic beta-lipoprotein fraction. The pure progestogen preparations were less advantageous because they in particular reduced the concentration of potentially anti-atherogenic alpha-lipoproteins.

Drospirenone for Oral Contraception and Hormone Replacement Therapy

The use of combined estrogen/progesterone has been shown to result in an increased cardiovascular risk in randomised double-blinded trials. However, these studies used oral progestogen (progestin) preparations, which lack anti-mineralocorticoid activity and have suboptimal anti-androgenic activity compared with progesterone. Drospirenone is a unique progestogen that has clinically been shown to have anti-mineralocorticoid/anti-androgenic effects. Drospirenone in combination with estrogen is currently being used for oral contraception and hormone replacement therapy, and has been shown to have favourable effects on a number of cardiovascular risk factors. Our review of the literature suggests that because of its anti-mineralocorticoid effects, drospirenone in conjunction with estrogen may prevent the development of cardiovascular disease in both pre- and post-menopausal women.

Breast cancer risk with postmenopausal hormonal treatment

This review was designed to determine from the best evidence whether there is an association between postmenopausal hormonal treatment and breast cancer risk. Also, if there is an association, does it vary according to duration and cessation of use, type of regimen, type of hormonal product or route of administration; whether there is a differential effect on risk of lobular and ductal cancer; and whether hormone treatment is associated with breast cancers that have better prognostic factors? Data sources for the review included Medline, the Cochrane Database of Systematic Reviews (Cochrane Library, 2005) and reference lists in the identified citations. Eligible citations addressed invasive breast cancer risk among postmenopausal women and involved use of the estrogen products with or without progestin that are used as treatment for menopausal symptoms. Abstracted data were demographic groupings, categories of hormone use, categories of breast cancer, two-by-two tables of exposure and outcome and adjusted odds ratios, relative risks (RRs) or hazard rates. Average estimates of risk were weighted by the inverse variance method, or if heterogeneous, using a random effects model. The average risk of invasive breast cancer with estrogen use was 0.79 [95% confidence interval (95% CI) = 0.61-1.02] in four randomized trials involving 12 643 women. The average breast cancer risk with estrogen-progestin use was 1.24 (95% CI = 1.03-1.50) in four randomized trials involving 19 756 women. The average risks reported in recent epidemiological studies were higher: 1.18 (95% CI = 1.01-1.38) with current use of estrogen alone and 1.70 (95% CI = 1.36-2.17) with current use of estrogen-progestin. The association of breast cancer with current use was stronger than the association with ever use, which includes past use. For past use, the increased breast cancer risk diminished soon after discontinuing hormones and normalized within 5 years. Reasonably adequate data do not show that breast cancer risk varies significantly with different types of estrogen or progestin preparations, lower dosages or different routes of administration, although there is a small difference between sequential and continuous progestin regimens. Epidemiological studies indicate that estrogen-progestin use increases risk of lobular more than ductal breast cancer, but the number of studies and cases of lobular cancer remains limited. Among important prognostic factors, the stage and grade in breast cancers associated with hormone use [corrected] do not differ significantly from those in non-users, but breast cancers in estrogen-progestin users are significantly more likely to be estrogen receptor (ER) positive. In conclusion, valid evidence from randomized controlled trials (RCTs) indicates that breast cancer risk is increased with estrogen-progestin use more than with estrogen alone. Epidemiological evidence involving more than 1.5 million women agrees broadly with the trial findings. Although new studies are unlikely to alter the key findings about overall breast cancer risk, research is needed, however, to determine the role of progestin, evaluate the risk of lobular cancer and delineate effects of hormone use on receptor presence, prognosis and mortality in breast cancer.

Do hormonal contraceptives stimulate growth of neurofibromas? A survey on 59 NF1 patients

BackgroundNeurofibromas are benign tumors of the peripheral nerves and hallmark of neurofibromatosis type 1 (NF1), a tumor suppressor gene syndrome. Neurofibromas mostly start developing at puberty and can increase in size and number during pregnancy. Expression of progesterone receptors has been found in 75% of the tumors. Many female NF1 patients are thus concerned about the possibility that hormonal contraceptives may stimulate the growth of their neurofibromas.MethodsA survey was carried out on 59 female NF1 patients who are practicing or have practiced hormonal contraception to examine the effect of the various contraceptives on the growth of neurofibromas.ResultsMajority (53 out of 58) of patients who received oral estrogen-progestogen or pure progestogen preparations reported no associated tumor growth. In contrast, significant tumor growth was reported by two patients who received depot contraceptive containing high dose of synthetic progesterone.ConclusionsOral contraceptives do not seem to stimulate the growth of neurofibromas in NF1 patients. High doses of progesterone might stimulate the growth of neurofibromas and deserve more caution.

Male hormonal contraception

Male hormonal contraception, based on the suppression of both gonadotropins, follicle-stimulating hormone and luteinizing hormone, resulting in marked decrease in sperm production, is designed for couples in stable relationships where the male partner desires to assume family planning responsibilities using reversible methods. Two large scale, multicenter studies that used testosterone injections as the prototype male hormonal contraceptive demonstrated when azoospermia and/or very severe oligozoospermia were attained, contraceptive efficacy was equivalent to female hormonal methods. Current studies aim to find the androgen alone or androgen plus progestin preparations that are most efficacious, user friendly, and with least potential adverse effects. It is likely that injections or implants of androgens either alone or with progestins will become the first male hormonal contraceptive available within this decade. Further research and development include the use of selective androgen and/or progestin receptor modulators, nonpeptide GnRH antagonists, and agents with local actions on the testis for male contraception.