Menopausal hormone therapy increases the risk of gallstones: Health Insurance Database in South Korea (HISK)-based cohort study.

OBJECTIVE: To determine whether menopausal hormone therapy (MHT) increases the risk of gallstones and gallbladder cancer. DESIGN: A retrospective cohort study. PATIENTS OR OTHER PARTICIPANTS: Data from the Korea National Health Insurance Corporation was obtained between January 1, 2002, and December 31, 2019. INTERVENTIONS: Participants were divided into MHT and non-MHT groups; the MHT group was analyzed in detail by dividing participants into tibolone, combined estrogen plus progestin by the manufacturer (CEPM) or physician (CEPP), oral estrogen alone, and topical estrogen subgroups. MAIN OUTCOME MEASURES: The incidence of gallstones and gallbladder cancer was compared between the two groups. RESULTS: This study enrolled 1,004,034 and 381,711 patients in the non-MHT and the MHT groups, respectively. The incidence of gallstones was 2.6% in the non-MHT group and 3.4%, 2.6%, 3.4%, 3.2%, and 4.4% in the tibolone, CEPM, oral estrogen alone, CEPP, and topical estrogen groups, respectively. Cox proportional hazard analysis revealed that all hormones increased the risk of gallstones ([tibolone] hazard ratio [HR]: 1.347, 95% confidence interval [CI]: 1.309-1.387, [CEPM] HR: 1.146, 95% CI: 1.1-1.19, [oral estrogen alone] HR: 1.241, 95% CI: 1.18-1.305, [CEPP] HR: 1.164, 95% CI: 1.01-1.341, [topical estrogen] HR: 1.602, 95% CI: 1.295-1.983). However, the risk of gallbladder cancer did not change with any hormone therapy. CONCLUSIONS: All types of MHT including tibolone, increased the risk of gallstones. This risk was the highest with topical estrogen, which may be a result of selection bias due to concerns regarding the adverse effects of CEE and MPA.

A new progestin-only pill (POP): the impact of drospirenone-only pill 4 mg 24 + 4 on coagulation markers and bleeding patterns.

PURPOSE: Progestin-only pills (POPs), compared to combined, are not associated with an increased risk of venous thromboembolism, but are associated with a poor cycle control. The aim of this study was to evaluate the impact of a new POP [4 mg drospirenone (DRSP) for 24 days with a 4-day hormone-free interval] on some coagulation markers (both procoagulant and fibrinolytic) and to describe its impact on bleeding patterns. MATERIALS AND METHODS: This is a prospective trial, based on serum evaluation of following coagulation markers and tests: Factor (F) X, F VIII, F V, INR, aPTT, Protein S and antithrombin III. A 'bleeding diary' was used to categorise women as having (1) unscheduled bleeding, (2) scheduled bleeding and (3) amenorrhoea. Thirty patients were followed for six 28-day intake cycles, with a follow-up at the end of the 3rd and 6th cycles. RESULTS: There was a significant decrease of F X (p = 0.03) (-5.7% at cycle 6). No significant changes have been observed for F VII, F V and INR. A significant increase in aPTT (p = 0.01 at 3 cycles), Protein S (p = 0.0006 at 3 cycles) and antithrombin III (p < 0.0001 at 3 cycles) was recorded. This non-deteriorating coagulation impact was associated with a significant and progressive reduction of days of scheduled and unscheduled bleeding in users between cycles 4 and 6 (from 1.3 ± 0.2 days at cycle 4 to 0.8 ± 0.1 days at cycle 6 and from 2.6 ± 0.4 days at cycle 4 to 0.6 ± 0.2 days at cycle 6, respectively, p < 0.0001). CONCLUSIONS: DRSP 24 + 4 use was associated with a non-deteriorating effect on coagulation markers and a significant progressive reduction of days of scheduled and unscheduled bleeding.

Contraception with DRSP 24 + 4 was associated with a non-deteriorating effect on coagulation markers and a significant progressive reduction of days of scheduled and unscheduled bleeding.

[Meningioma under progestin treatment : what attitude to adopt ?] / Méningiome sous traitement progestatif : quelle attitude adopter ?

The risks of meningioma associated with the use of cyproterone acetate at high doses (25 to 100 mg/day) have been known since 2007. Recently, two additional molecules have been incriminated: nomegestrol acetate and chlormadinone acetate. The higher the cumulative dose and the longer the treatment duration, the bigger the risk of meningioma (12-fold after 5 years of treatment for nomegestrol acetate, and 7-fold after 3.5 years of treatment for chlormadinone acetate). Nevertheless, these medications have many indications that demonstrate their importance in the daily practice of the general practitioner, of the gynecologist and of the reproductive endocrinologist. Therefore, caution is required when introducing a powerful progestin that is incriminated in the long term at high doses. If the benefit/risk balance favours the initiation of progestin therapy, it is recommended to use the minimal effective dose and to limit the duration of use. Clinical and brain imaging monitoring should also be performed. Finally, if a meningioma develops on progestin, it is recommended that any medication containing a progesterone agonist be suspended.

Les risques de méningiome liés à la consommation de l'acétate de cyprotérone à de fortes doses (25 à 100 mg/jour) sont connus depuis 2007. Récemment, deux molécules supplémentaires ont été incriminées : l'acétate de nomégestrol et l'acétate de chlormadinone. Le risque de développer un méningiome est d'autant plus important que la dose cumulée est grande et que la prescription se prolonge dans le temps (risque multiplié par 12 à partir de 5 ans de traitement pour l'acétate de nomégestrol, et multiplié par 7 à partir de 3,5 ans de traitement par acétate de chlormadinone). Néanmoins, ces médications possèdent de nombreuses indications témoignant de leur importance dans la pratique quotidienne du médecin généraliste, du gynécologue et de l'endocrinologue de la reproduction. Dès lors, la vigilance est de mise lors de l'introduction d'un progestatif puissant incriminé à long terme et à haute dose. Si la balance bénéfices/risques plaide en faveur de l'instauration d'un traitement par progestatif, il est recommandé d'utiliser la dose minimale efficace et d'en limiter la durée d'utilisation. Une surveillance clinique et par imagerie cérébrale systématique est vivement recommandée. Enfin, en cas de détection d'un méningiome, il est recommandé de suspendre toute médication contenant un agoniste de la progestérone.

Navigating a plethora of progesterone receptors: Comments on the safety/risk of progesterone supplementation in women with a history of breast cancer or at high-risk for developing breast cancer.

Progesterone and progestin agonists are potent steroid hormones. There are at least three major types of progesterone receptor (PR) families that interact with and respond to progesterone or progestin ligands. These receptors include ligand-activated transcription factor isoforms (PR-A and PR-B) encoded by the PGR gene, often termed classical or nuclear progesterone receptor (nPR), membrane-spanning progesterone receptor membrane component proteins known as PGRMC1/2, and a large family of progestin/adipoQreceptors or PAQRs (also called membrane PRs or mPRs). Cross-talk between mPRs and nPRs has also been reported. The complexity of progesterone actions via a plethora of diverse receptors warrants careful consideration of the clinical applications of progesterone, which primarily include birth control formulations in young women and hormone replacement therapy following menopause. Herein, we focus on the benefits and risk of progesterone/progestin supplementation. We conclude that progesterone-only supplementation is considered safe for most reproductive-age women. However, women who currently have ER + breast cancer or have had such cancer in the past should not take sex hormones, including progesterone. Women at high-risk for developing breast or ovarian cancer, either due to their family history or known genetic factors (such as BRCA1/2 mutation) or hormonal conditions, should avoid exogenous sex hormones and proceed with caution when considering using natural hormones to mitigate menopausal symptoms and/or improve quality of life after menopause. These individuals are urged to consult with a qualified OB-GYN physician to thoroughly assess the risks and benefits of sex hormone supplementation. As new insights into the homeostatic roles and specificity of highly integrated rapid signaling and nPR actions are revealed, we are hopeful that the benefits of using progesterone use may be fully realized without an increased risk of women's cancer.

Over-the-Counter Progestin-Only Oral Contraceptives.

This JAMA Patient Page describes progestin-only oral contraceptive pills, which recently have been approved to be sold over the counter.

Lack of evidence that progesterone in ovulatory cycles causes breast cancer.

A recent Perspective article asserted that progesterone secretion during ovulatory cycles is the cause of breast cancer. However, we challenge most of the evidence developed in this publication. First, there is a lack of evidence that progesterone is mutagenic for breast cells. Cause of a cancer should mean initiation by mutation, as opposed to promotion. Second, subclinical ovulatory disturbances occur rather frequently in normal-length menstrual cycles. Third, the authors attribute a potential carcinogenic effect to progesterone secreted during menstrual cycles but not to progesterone during pregnancy. They did not discuss breast cancer evidence from progesterone/progestin therapeutics. They argue that in genetic primary amenorrhea, a hypothetic lower risk of breast cancer could be due to the lack of progesterone, despite the progesterone/progestin in hormone replacements these women receive. Fourth, they advocate a regulatory effect of progesterone on several genes potentially involved in cancer genesis. In particular, they attribute a lower risk of breast cancer in women with Mayer-Rokitansky-Küster-Hauser syndrome to a defect in the progesterone-stimulated Wnt4 gene. However, this defect is only present in a small subset. Thus, the postulated progesterone breast cancer risk is unconvincing, which we discuss point by point in this commentary.

Former long-term use of combined hormonal contraception and glucose metabolism disorders in perimenopausal women: A prospective, population-based cohort study.

INTRODUCTION: Current use of combined hormonal contraceptives worsens glucose tolerance and increases the risk of type 2 diabetes mellitus at late fertile age, but the impact of their former use on the risk of glucose metabolism disorders is still controversial. MATERIAL AND METHODS: This was a prospective, longitudinal birth cohort study with long-term follow-up consisting of 5889 women. The cohort population has been followed at birth, and at ages of 1, 14, 31 and 46. In total, 3280 (55.7%) women were clinically examined and 2780 also underwent a 2-h oral glucose tolerance test at age 46. Glucose metabolism indices were analyzed in former combined hormonal contraceptive users (n = 1371) and former progestin-only contraceptive users (n = 52) and in women with no history of hormonal contraceptive use (n = 253). RESULTS: Compared with women with no history of hormonal contraceptive use, those who formerly used combined hormonal contraceptives for over 10 years had an increased risk of prediabetes (odds ratio [OR] 3.9, 95% confidence interval [CI]: 1.6-9.2) but not of type 2 diabetes mellitus. Former progestin-only contraceptive use was not associated with any glucose metabolism disorders. The results persisted after adjusting for socioeconomic status, smoking, alcohol consumption, parity, body mass index and use of cholesterol-lowering medication. CONCLUSIONS: Former long-term use of combined hormonal contraceptives was associated with a significantly increased risk of prediabetes in perimenopausal women, which potentially indicates a need of screening for glucose metabolism disorders in these women.

Retrospective Analysis of Sugammadex Use in Adolescent Females on Progestin-Containing Contraceptives.

STUDY OBJECTIVE: Sugammadex, a novel neuromuscular blockade reversal agent, functions as a steroid binder postulated to decrease hormone exposure used within progestin-containing contraceptive medications. Thus, alternative non-medication contraceptive methods are recommended to prevent unplanned pregnancies. The study aims were to evaluate sugammadex use in adolescent females prescribed a progestin-containing contraceptive and positive pregnancy screening frequency. We hypothesized that sugammadex use is infrequent in this population and no pregnancy screens would be positive. METHODS: This is a retrospective observational cohort study utilizing the TriNetX electronic health record database of female subjects aged 12-21 years reported to be prescribed sugammadex. The data collected were analyzed for demographic characteristics, International Classification of Diseases 9th and 10th edition diagnostics, medication, procedural codes, progestin-containing medication timing, and timing of pregnancy screening. RESULTS: We included 18,686 subjects (contraceptive group, 2017 [10.8%], and no contraceptive group, 16,669 [89.2%]). Both groups had similar frequencies of pregnancy screening (contraceptive group, 54 [2.7%], vs no contraceptive group, 366 [2.2%]). Of the contraceptive group, 1 (0.05%) subject, 17 years of age, was confirmed to have a positive pregnancy screen 35 days after surgery. CONCLUSION: We found that sugammadex may be administered to adolescent females prescribed progestin-containing contraceptives, but positive pregnancy screens are rare. Effective counseling, use of nonhormonal contraceptives 7 days after sugammadex administration, and the theoretical reproductive risks of this agent may have contributed to these findings. Continued counseling after sugammadex use in the adolescent population is recommended to avoid the occurrence of unplanned pregnancies.

Menopausal hormone therapy and dementia: nationwide, nested case-control study.

OBJECTIVES: To assess the association between use of menopausal hormone therapy and development of dementia according to type of hormone treatment, duration of use, and age at usage. DESIGN: Nationwide, nested case-control study. SETTING: Denmark through national registries. PARTICIPANTS: 5589 incident cases of dementia and 55 890 age matched controls were identified between 2000 and 2018 from a population of all Danish women aged 50-60 years in 2000 with no history of dementia or contraindications for use of menopausal hormone therapy. MAIN OUTCOME MEASURES: Adjusted hazard ratios with 95% confidence intervals for all cause dementia defined by a first time diagnosis or first time use of dementia specific medication. RESULTS: Compared with people who had never used treatment, people who had received oestrogen-progestogen therapy had an increased rate of all cause dementia (hazard ratio 1.24 (95% confidence interval 1.17 to 1.33)). Increasing durations of use yielded higher hazard ratios, ranging from 1.21 (1.09 to 1.35) for one year or less of use to 1.74 (1.45 to 2.10) for more than 12 years of use. Oestrogen-progestogen therapy was positively associated with development of dementia for both continuous (1.31 (1.18 to 1.46)) and cyclic (1.24 (1.13 to 1.35)) regimens. Associations persisted in women who received treatment at the age 55 years or younger (1.24 (1.11 to 1.40)). Findings persisted when restricted to late onset dementia (1.21 (1.12 to 1.30)) and Alzheimer's disease (1.22 (1.07 to 1.39)). CONCLUSIONS: Menopausal hormone therapy was positively associated with development of all cause dementia and Alzheimer's disease, even in women who received treatment at the age of 55 years or younger. The increased rate of dementia was similar between continuous and cyclic treatment. Further studies are warranted to determine whether these findings represent an actual effect of menopausal hormone therapy on dementia risk, or whether they reflect an underlying predisposition in women in need of these treatments.

Menopause hormone treatment after cancer.

Regular improvement in survival of women after treatment for cancer has been reached in these last years. Menopause hormone therapy (MHT) remains the most efficient treatment to alleviate climacteric symptoms and improve quality of life in symptomatic women. The long-term effects of estrogen deficiency can be, at least partially, prevented by MHT. However, using MHT in an oncologic context can be associated with contraindications. Patients who have experienced breast cancer frequently face severe climacteric symptoms, but results from randomized trials are not in favor of using MHT in these women. Three randomized trials are available in women treated by MHT after ovarian cancer, and report better survival rates in the active group of treatment, suggesting that, at least in serous high-grade ovarian carcinoma, MHT could be allowed. No robust data are available for MHT after endometrial carcinoma. According to various guidelines, MHT could be possible in low grades with good prognosis. Progestogen, however, is not contraindicated and can help to alleviate climacteric symptoms. Squamous cell cervical carcinoma is not hormone-dependent and therefore patients can be treated with MHT without restrictions, whereas cervical adenocarcinoma is likely to be estrogen-dependent, despite lack of robust data, and thus only progesterone or progestin might be potentially used. It is possible that, in future, better molecular characterization of genomic profiles of various cancers may allow MHT to be used with some patients.

Combined and progestagen-only hormonal contraceptives and breast cancer risk: A UK nested case-control study and meta-analysis.

BACKGROUND: Current or recent use of combined oral contraceptives (containing oestrogen+progestagen) has been associated with a small increase in breast cancer risk. Progestagen-only contraceptive use is increasing, but information on associated risks is limited. We aimed to assess breast cancer risk associated with current or recent use of different types of hormonal contraceptives in premenopausal women, with particular emphasis on progestagen-only preparations. METHODS AND FINDINGS: Hormonal contraceptive prescriptions recorded prospectively in a UK primary care database (Clinical Practice Research Datalink [CPRD]) were compared in a nested case-control study for 9,498 women aged <50 years with incident invasive breast cancer diagnosed in 1996 to 2017, and for 18,171 closely matched controls. On average, 7.3 (standard deviation [SD] 4.6) years of clinical records were available for each case and their matched controls prior to the date of diagnosis. Conditional logistic regression yielded odds ratios (ORs) and 95% confidence intervals (CIs) of breast cancer by the hormonal contraceptive type last prescribed, controlled for age, GP practice, body mass index, number of recorded births, time since last birth, and alcohol intake. MEDLINE and Embase were searched for observational studies published between 01 January 1995 and 01 November 2022 that reported on the association between current or recent progestagen-only contraceptive use and breast cancer risk in premenopausal women. Fixed effects meta-analyses combined the CPRD results with previously published results from 12 observational studies for progestagen-only preparations. Overall, 44% (4,195/9,498) of women with breast cancer and 39% (7,092/18,171) of matched controls had a hormonal contraceptive prescription an average of 3.1 (SD 3.7) years before breast cancer diagnosis (or equivalent date for controls). About half the prescriptions were for progestagen-only preparations. Breast cancer ORs were similarly and significantly raised if the last hormonal contraceptive prescription was for oral combined, oral progestagen-only, injected progestagen, or progestagen-releasing intrauterine devices (IUDs): ORs = 1.23 (95% CI [1.14 to 1.32]; p < 0.001), 1.26 (95% CI [1.16 to 1.37]; p < 0.001), 1.25 (95% CI [1.07 to 1.45]; p = 0.004), and 1.32 (95% CI [1.17 to 1.49]; p < 0.001), respectively. Our meta-analyses yielded significantly raised relative risks (RRs) for current or recent use of progestagen-only contraceptives: oral = 1.29 (95% CI [1.21 to 1.37]; heterogeneity χ25 = 6.7; p = 0.2), injected = 1.18 (95% CI [1.07 to 1.30]; heterogeneity χ28 = 22.5; p = 0.004), implanted = 1.28 (95% CI [1.08 to 1.51]; heterogeneity χ23 = 7.3; p = 0.06), and IUDs = 1.21 (95% CI [1.14 to 1.28]; heterogeneity χ24 = 7.9; p = 0.1). When the CPRD results were combined with those from previous published findings (which included women from a wider age range), the resulting 15-year absolute excess risk associated with 5 years use of oral combined or progestagen-only contraceptives in high-income countries was estimated at: 8 per 100,000 users from age 16 to 20 years and 265 per 100,000 users from age 35 to 39 years. The main limitation of the study design was that, due to the nature of the CPRD data and most other prescription databases, information on contraceptive use was recorded during a defined period only, with information before entry into the database generally being unavailable. This means that although our findings provide evidence about the short-term associations between hormonal contraceptives and breast cancer risk, they do not provide information regarding longer-term associations, or the impact of total duration of contraceptive use on breast cancer risk. CONCLUSIONS: This study provides important new evidence that current or recent use of progestagen-only contraceptives is associated with a slight increase in breast cancer risk, which does not appear to vary by mode of delivery, and is similar in magnitude to that associated with combined hormonal contraceptives. Given that the underlying risk of breast cancer increases with advancing age, the absolute excess risk associated with use of either type of oral contraceptive is estimated to be smaller in women who use it at younger rather than at older ages. Such risks need be balanced against the benefits of using contraceptives during the childbearing years.

Abnormal Uterine Bleeding during Pubertal Induction with Transdermal Estrogen in Individuals with Turner Syndrome.

STUDY OBJECTIVE: Incidence of abnormal uterine bleeding (AUB) during pubertal induction among individuals with Turner syndrome (TS) has not been described previously. We estimated the incidence and characterized factors associated with AUB among individuals with TS. A secondary objective was to evaluate the management of AUB among this patient population. DESIGN, SETTING, PARTICIPANTS, AND INTERVENTION: We conducted a retrospective chart review to evaluate individuals with TS undergoing hormone replacement therapy (HRT) for pubertal induction with transdermal estrogen. A total of 45 participants were identified between January 2007 and June 2019. RESULTS: Of the 45 individuals with TS included, 16 (35%) experienced AUB. Individuals with AUB most commonly experienced prolonged (44%), prolonged and heavy (25%), and intermenstrual (19%) bleeding. Individuals who experienced AUB were more likely to experience spontaneous bleeding (69% vs 28%) and a duration of unopposed estrogen greater than 18 months (63% vs 41%), undergo progestin cycling less often than monthly (69% vs 0%), use a micronized progestin dose of less than 200 mg (25% vs 14%), and be noncompliant with HRT (19% vs 0%) compared with those who did not experience AUB. CONCLUSION: There is a relatively high incidence of AUB among individuals with TS undergoing pubertal induction with transdermal estrogen. Care providers should consider the clinical factors examined to guide monitoring and management of individuals with TS on HRT.

Opposed evolution of the osseous and soft parts of progestin-associated osteomeningioma after progestin intake discontinuation.

OBJECTIVE: Numerous studies have confirmed a strong association between progestins and meningiomas and the regression and/or stabilization of meningiomas after discontinuation of treatment. Osteomeningiomas represent a small subgroup of meningiomas that appear to be more common among progestin-related meningiomas. However, the specificity of the behavior of this subset of meningiomas after discontinuation of progestin has not yet been assessed. METHODS: Thirty-six patients (mean age 49.5 years) who presented with at least one progestin-related osteomeningioma (48 tumors total) were identified from a prospectively collected database of patients and had been referred to our department for meningioma and had documented use of cyproterone acetate, nomegestrol acetate, and/or chlormadinone acetate. Hormonal treatment was stopped at the time of diagnosis for all the patients, and the clinical and radiological evolution of this subgroup of tumors was evaluated. RESULTS: For half of the 36 patients, treatment was prescribed for signs of hyperandrogenism, such as hirsutism, alopecia, or acne. Most lesions were spheno-orbital (35.4%) or frontal (31.2%). Although the tissular part of the meningioma shrank in 77.1% of cases, the osseous part exhibited discordant behavior with 81.3% showing volume progression. The combination of estrogens, as well as the prolonged duration of progestin treatment, seems to increase the risk of progression of the osseous part after treatment discontinuation (p = 0.02 and p = 0.028, respectively). No patient required surgical treatment at diagnosis or during the study. CONCLUSIONS: These results show that while the soft intracranial part of progestin-related osteomeningioma tumor is the most likely to regress after treatment discontinuation, the bony part is more likely to increase in volume. These findings suggest the need for careful follow-up of these patients, especially those with tumors near the optical apparatus.

[Combined Hormonal Contraception - Which Pill for Which Patient?] / Kombinierte hormonelle Kontrazeption ­ welches Präparat für welche Indikation?

Combined Hormonal Contraception - Which Pill for Which Patient? Abstract. Combined hormonal contraceptives (CHC) are a valuable and highly effective option in contraceptive counseling. Methods and preparations available in Switzerland are combined oral contraceptives (COC), vaginal rings and transdermal patches. All preparations contain an estrogen and a progestin component. The estrogen component mainly consists of the synthetically produced ethinylestradiol (EE), although newer COC may contain natural estrogens such as estradiol (E2) and estetrol (E4). For the progestin component, a variety of luteal body hormones are available, which enable the health care professional to prescribe a "tailored" product for the patient due to their different partial effects. The individual thromboembolism (TE) risk should always be considered and taken into account when prescribing CHC.

Menopausal hormone therapy and the risk of type 2 diabetes mellitus: Health Insurance Database in South Korea-based retrospective cohort study.

OBJECTIVE: Menopausal hormone therapy (MHT) is known to reduce the incidence of type 2 diabetes mellitus (T2DM); however, since the Women's Health Initiative study, the types and doses of female hormones used for MHT have changed considerably. Therefore, this study was conducted to determine whether MHT, which is currently widely prescribed, increases the risk of T2DM. METHOD: We performed a retrospective cohort study based on national health insurance data and cancer screening data from 2002 to 2019. We included the MHT group as postmenopausal women older than 40 years who used at least one MHT for at least 6 months between 2003 and 2011. We subclassified the MHT group into five categories; tibolone, combined estrogen plus progestin by the manufacturer (CEPM), oral estrogen, combined estrogen plus progestin by the physician (CEPP), and transdermal estrogen. We selected the non-MHT group as postmenopausal women who had never been prescribed MHT from 2002 to 2019. We compared the incidence of T2DM between the MHT group and the non-MHT group. RESULTS: We enrolled 330,771 women in the MHT group and 798,550 women in the control group. T2DM was diagnosed in 15.2% of the non-MHT group, 16.6% of the tibolone group, 12.1% of the CEPM group, 16.6% of the oral estrogen group, 15.4% of the CEPP group, and 17% of the transdermal estrogen group. In Cox proportional hazard analysis adjusted for variable factors, tibolone, oral estrogen, CEPP, and transdermal estrogen increased the incidence of T2DM. In contrast, there was no change in the risk of T2DM in the CEPM group. CONCLUSIONS: MHT, including tibolone, which is currently the most prescribed agent, increased the risk of T2DM; however, CEPM did not increase the risk of T2DM. Only tibolone increased the risk of T2DM in participants older than 70 years.

Endometrial cancer risk with menopausal hormone therapy: Health Insurance Database in South Korea-based cohort study.

OBJECTIVE: To determine the risk of endometrial cancer according to the types of menopausal hormones used. METHODS: This retrospective cohort study recruited postmenopausal women older than 40 years from 2003 to 2011, utilizing data from the Korean national health insurance system from 2002 to 2019. The menopausal hormone therapy (MHT) group consisted of women who had been prescribed MHT for greater than 6 months between 2003 and 2011. The non-MHT group consisted of women who had never used menopausal hormones between 2003 and 2011. RESULTS: A non-MHT group of 1 000 550 women and a MHT group of 353 025 women were chosen. In comparison to never-users, the risk of endometrial cancer was not higher in women who reported last using tibolone (adjusted hazard ratio [aHR] 1.08, 95% confidence interval [CI] 0.96-1.2), combined estrogen plus progestin by the manufacturer (aHR 0.83, 0.72-0.96), combined estrogen plus progestin by the physician (aHR 0.88, 0.7-1.12), and transdermal estrogen (aHR 1.13, 0.36-3.52). CONCLUSIONS: Tibolone, combined estrogen plus progestin by the physician, and transdermal estrogen do not affect the risk of endometrial cancer. The combination of estrogen plus progestin by the manufacturer decreases the risk of endometrial cancer.

Autism-like behavior of murine offspring induced by prenatal exposure to progestin is associated with gastrointestinal dysfunction due to claudin-1 suppression.

Autism spectrum disorders (ASD) are associated with the contribution of many prenatal risk factors; in particular, the sex hormone progestin and vitamin D receptor (VDR) are associated with gastrointestinal (GI) symptoms in ASD development, although the related mechanism remains unclear. We investigated the possible role and mechanism of progestin 17-hydroxyprogesterone caproate (17-OHPC) exposure-induced GI dysfunction and autism-like behaviours (ALB) in mouse offspring. An intestine-specific VDR-deficient mouse model was established for prenatal treatment, while transplantation of haematopoietic stem cells (HSCT) with related gene manipulation was used for postnatal treatment for 17-OHPC exposure-induced GI dysfunction and ALB in mouse offspring. The in vivo mouse experiments found that VDR deficiency mimics prenatal 17-OHPC exposure-mediated GI dysfunction, but has no effect on 17-OHPC-mediated autism-like behaviours (ALB) in mouse offspring. Furthermore, prenatal 17-OHPC exposure induces CLDN1 suppression in intestine epithelial cells, and transplantation of HSCT with CLDN1 expression ameliorates prenatal 17-OHPC exposure-mediated GI dysfunction, but has no effect on 17-OHPC-mediated ALB in offspring. In conclusion, prenatal 17-OHPC exposure triggers GI dysfunction in autism-like mouse offspring via CLDN1 suppression, providing a possible explanation for the involvement of CLDN1 and VDR in prenatal 17-OHPC exposure-mediated GI dysfunction with ASD.

Hysterectomy, bilateral oophorectomy, and breast cancer risk in a racially diverse prospective cohort study.

BACKGROUND: Gynecologic surgery is hypothesized to reduce risk of breast cancer; however, associations may be modified by subsequent hormone use. Our objective was to examine the association between gynecologic surgery and breast cancer incidence considering the use of hormone therapy. METHODS: The Sister Study is a prospective cohort of initially breast cancer-free women aged 35-74 years with a sister who had breast cancer. We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between gynecologic surgery (no surgery, hysterectomy only, bilateral oophorectomy with or without hysterectomy) and incident breast cancer among 50 701 women. RESULTS: History of gynecologic surgery was common, with 13.8% reporting hysterectomy only and 18.1% reporting bilateral oophorectomy with or without hysterectomy. During follow-up (median = 11.4 years), 3948 cases were diagnosed. Compared with no surgery, bilateral oophorectomy was inversely associated with breast cancer (HR = 0.91, 95% CI = 0.83 to 1.00), and hysterectomy alone was positively associated (HR = 1.12, 95% CI = 1.02 to 1.23). Compared with no surgery and no hormone therapy, bilateral oophorectomy combined with estrogen only therapy (HR = 0.83, 95% CI = 0.74 to 0.94) was inversely associated with breast cancer, while hysterectomy combined with estrogen plus progestin therapy was positively associated with breast cancer (HR = 1.25, 95% CI = 1.01 to 1.55). CONCLUSIONS: We observed an inverse association between bilateral oophorectomy and breast cancer risk. The positive association between hysterectomy and breast cancer may be due to concomitant estrogen plus progestin therapy.

A focused report on progestogen hypersensitivity.

INTRODUCTION: Progestogen Hypersensitivity (PH) is caused by increased sensitivity to either exogenous or endogenous progestogens. It is characterized by recurrent cutaneous eruptions including erythema multiforme, eczema, urticaria, and angioedema, which may be associated with systemic symptoms including asthma and anaphylaxis. AREAS COVERED: Symptoms may be persistent or cyclical, coinciding with progestogen levels. With increased use of oral contraceptives and hormonal treatments for fertility, the prevalence of PH is expected to continuously increase. Several proposed immunological mechanisms, diagnostics, and treatment modalities have been proposed. Most treatments focus on suppressing ovulation and progesterone secretion or inducing tolerance through progesterone desensitization. EXPERT OPINION: Although there has been increased recognition both clinically and in the medical literature, there is still a general lack of knowledge of PH and its clinical features in the medical community. An improved understanding of the underlying pathophysiology as well as more available commercial testis, such as ELISA that accurately measures specific IgE to progesterone, are expected to broaden and improve opportunities for disease recognition and symptom control. It is essential for physicians across specialties to recognize how to diagnose PH and either manage this condition or refer these patients to a specialist with experience treating PH.

Use of menopausal hormone therapy and ovarian cancer risk in a French cohort study.

BACKGROUND: Epidemiological studies have found that menopausal hormone therapy (MHT) use is associated with an increased ovarian cancer risk. However, whether different MHT types confer the same level of risk is unclear. We estimated the associations between different MHT types and the risk of ovarian cancer in a prospective cohort. METHODS: The study population included 75 606 postmenopausal women from the E3N cohort. Exposure to MHT was identified from self-reports in biennial questionnaires between 1992 and 2004 and from drug claim data matched to the cohort between 2004 and 2014. Hazard ratios and 95% confidence intervals (CIs) of ovarian cancer were estimated using multivariable Cox proportional hazards models with MHT as a time-varying exposure. Tests of statistical significance were 2-sided. RESULTS: Over an average 15.3 years follow-up, 416 ovarian cancers were diagnosed. Hazard ratios of ovarian cancer associated with ever use of estrogens combined with progesterone or dydrogesterone and ever use of estrogens combined with other progestagen were equal to 1.28 (95% CI = 1.04 to 1.57) and 0.81 (95% CI = 0.65 to 1.00), respectively (Phomogeneity = .003), compared with never use. The hazard ratio for unopposed estrogen use was 1.09 (95% CI = 0.82 to 1.46). We found no trend according to duration of use or time since last use except for estrogens combined with progesterone or dydrogesterone, which showed decreasing risk with increasing time since last use. CONCLUSION: Different MHT types may impact ovarian cancer risk differentially. The possibility that MHT containing progestagens other than progesterone or dydrogesterone may confer some protection should be evaluated in other epidemiological studies.