Hormone Replacement Therapy Preparations Research Articles

Premature ovarian insufficiency

Key content: Premature ovarian insufficiency (POI) is a clinical syndrome involving ovarian follicle depletion and defined by loss of ovarian function before 40 years of age. The diagnostic workup in women with suspected POI is in two steps: confirming the diagnosis and establishing its cause; it is important to understand the rationale for performing each diagnostic test, how to interpret results and appropriate multidisciplinary team involvement. Treatment options include various regimens and preparations of hormone replacement therapy (HRT), monitoring and surveillance, induction of puberty in those with very early POI, complimentary treatment and fertility treatment. Management of POI requires a comprehensive and personalised strategy that addresses not only the physical symptoms and disease risks, but also the psychosocial and reproductive health aspects, and it is important that women receive adequate counselling. Learning objectives: To raise awareness of early diagnosis of POI. To be able to discuss the implications of POI for the health of women affected and their families, as well as for different hormonal and non‐hormonal treatment options. To understand various fertility treatment options for POI. Ethical issues: It is important to consider the reproductive and diagnostic implications for women with chromosomal or genetic problems (e.g. Turner syndrome, Fragile X mutation carriers) and for their family members. A diagnosis of POI may have differing implications based on social and cultural factors, and healthcare providers should consider a patient's values, beliefs, cultural background and preferences.

Management of menopause in women with a history of endometriosis.

Due to increasing life expectancy, women spend a significant part of their lives in menopause. Women with a history of endometriosis are more likely to become menopausal at an early age due to bilateral oophorectomy or repeated ovarian surgery. In addition, some medical therapies used for endometriosis, such as gonadotropin releasing hormone agonists or progestins reduce bone mineral density. Furthermore, women with endometriosis have a higher background risk of cardiovascular disorders and hypercholesterolemia. Hence, it is important to recommend the use of hormone replacement therapy (HRT) to these women when they become menopausal, at least until the age of natural menopause. Although based on limited data, there is a possibility of reactivation of symptoms of endometriosis or its lesions, and a theoretical possibility of malignant transformation, although this remains unproven. Therefore, women should be advised in the light of this information before starting HRT after the age of natural menopause and are asked to seek help if they experience symptoms that may indicate these changes. Estrogen only HRT should be avoided and combined HRT preparations should be recommended, even after a hysterectomy.

P-109 Letrozole versus hormone replacement therapy for frozen embryo transfer: A randomized clinical trial

Abstract Study question Do the outcomes of frozen embryo transfer cycles differ according to endometrial preparation (EP) with letrozole versus hormone replacement therapy (HRT)? Summary answer Letrozole seems to be as effective as HRT preparation in frozen cycles in terms of treatment outcomes. What is known already Vitrification improved the survival of vitrified-warmed embryos and increased the number of FET cycles. A common EP strategy for FET includes augmentation of the endometrium using estrogen followed by progesterone supplements. Retrospective studies have shown that using aromatase inhibitors (letrozole) in FET cycles was associated with higher clinical pregnancy and live birth rates, with a lower miscarriage rate, as compared to HRT cycles. Letrozole maintains regular feedback mechanisms, facilitating normal follicular growth, and promotes single follicle development and ovulation. Moreover, it does not have any negative effects on the endometrium and can improve endometrial receptivity. Study design, size, duration This randomized controlled trial was performed in two university-affiliated medical centers. A total of 170 patients undergoing frozen embryo transfer cycles from June 2018 to June 2021 were eligible. Participants/materials, setting, methods Patients were randomized to either letrozole (n = 69) or HRT protocol (n = 101) for EP, using a blocked randomization method. Inclusion criteria were single blastocyst transfer with normal uterine cavity. Exclusion criteria were patients older than 40 years, oocyte donation cycles, or more than 3 previous transfers without a pregnancy. The primary study outcome was percentage of clinical pregnancies, defined as clinical pregnancies/embryo transfers, excluding canceled treatments. Main results and the role of chance The characteristics of the study groups were comparable in age, BMI, gravidity, parity, previous treatment history and characteristics of the relevant fresh cycle in which the embryo was frozen. After excluding 5 cancelled treatments in the letrozole group and 2 in the HRT group, the percentage of clinical pregnancies between the letrozole and HRT arms were similar (24 (38.0%) versus 34 (34.6%), respectively, p = 0.67). There was no difference in the percentages of live births (22 (34.9%) versus 28 (28.6%), respectively, p = 0.4) or missed abortions (1 (4.1%) versus 5 (14.7%), p = 0.19). For patients who did not achieve pregnancy in the randomized treatment cycle, we retrospectively examined the outcome of the next treatment cycle with the other EP protocol, when possible. Achievement of a clinical pregnancy was the same for change in treatment for both study groups (7(50%) in the letrozole group and 9(50%) in the HRT group). Limitations, reasons for caution Limitations of this study included the heterogeneous study groups. Even though class II ovulation disorders were similar in prevalence in both groups, they included different indications for ART. Pregnancy complications were not evaluated and should be further investigated in a study with a larger sample size. Wider implications of the findings Letrozole seems to be as effective as HRT for EP in frozen cycles, with possible advantages of fewer missed abortions and pregnancy complications. Letrozole could be a suitable option for EP, as it is effective and, enables more convenient timing, versus natural FET. Trial registration number NCT03540979

O-022 Shall we go “natural” for endometrial preparation in egg donation programs? Live birth rates and obstetrical outcome from 797 frozen single-blastocyst transfers cycles

Abstract Study question Frozen single blastocyst transfer in modified natural cycle (mNC) increases success rates reducing obstetric risks in egg recipients, compared to Hormone Replacement Therapy (HRT) protocols? Summary answer In egg recipients, single-blastocyst transfer in mNC showed higher pregnancy rates, lower miscarriage rates, higher new-born rates compared to HRT, being preterm birth rate comparable. What is known already When choosing endometrial preparation protocols for egg recipients, we must consider medication safety and costs, cycle’s cancellation rate, clinical outcomes as maternal and fetal risks. The superiority of mNC over HRT for frozen embryo transfers (FET) has been reported in terms of delivery and miscarriage rates as well as obstetrical complications, but few data are available on egg recipients, being HRT protocols the routine treatment in most cases. In donor programs, when a blastocyst freeze-all strategy or egg banking is applied, there is no longer need for donor-recipient synchronization and many FET could be performed in mNC cycles. Study design, size, duration Retrospective single-centre comparative clinical study, including 797 frozen single-blastocyst transfer (FSBT) initiated cycles between January 2020 and December 2021: 590 (74%) in HRT protocol and 207 (26%) in mNC protocol. The two groups were homogeneous for donor’s age (25,4 yo HRT Vs 25,8 yo mNC), recipient’s age (42,1 yo HRT Vs 42,4 yo mNC), severe male factor (6% HRT Vs 4% mNC), and the need for a sperm donor (28% HRT Vs 22% mNC). Participants/materials, setting, methods Among 797 started cycles, we compared cancellation rates between HRT and mNC groups due to either medical reasons (inadequate endometrium, bleeding, ovulatory leak) or other issues (no embryo survival, flight cancellations, COVID-19 restrictions). We studied the clinical outcomes of the 683 FSBT performed, comparing HRT and mNC cycles for pregnancy rate, clinical pregnancy rate, miscarriage rate, live birth rate, and preterm birth rate <35 weeks. We used Chi-square test to compare groups (p < 0,05). Main results and the role of chance CANCELLATION RATES: Out of the 797 endometrial preparation cycles started, the overall cancellation rate was 14% from which 72,8% due to medical reasons (inadequate endometrium, bleeding, ovulatory leak) and 27,2% due to other issues (no embryo survival, SARS-Cov-2 related issues, flight cancellations, etc.); when evaluating cancellation for medical reasons, we didn’t find significant differences between HRT protocol cycles (9%) and mNC protocol cycles (7%), p = 0,33. CLINICAL OUTCOMES: Out of the 683 frozen single blastocyst transfers performed, no twin pregnancies occurred as expected. There were no statistically significant differences between HRT Vs mNC endometrial preparation protocol when comparing pregnancy rates (59% Vs 63%, p = 0,35), clinical pregnancy rates (49% Vs 57%, p = 0,10) and miscarriage rates (19% Vs 16%, p = 0,48). Live birth rate was significantly higher in the mNC (47%) compared to HRT (38%), p = 0,046. Overall preterm birth rate <35 weeks was 3,9%, including <32 weeks 1,1% and <28 weeks 0,3%. There were no significant differences between HRT and mNC endometrial preparation protocol for preterm birth rate <35 weeks (3,6% Vs 4,6%, p = 0,75). Limitations, reasons for caution Single-centre retrospective comparative trial. Homogeneity studies included several confounding variables, but other bias could have been studied such as uterine factor, PGT-A rate or previous fertility treatments. Wider implications of the findings In donor programs, the use of modified natural cycle should be encouraged as first option irrespectively from recipient’s age for FET in normo-ovulatory patients, considering the increased live birth rates when compared to HRT-FET cycles. Moreover, mNC cycles are more patient’s friendly and cost-effective. Trial registration number not applicable

Hormone replacement therapy in women with history of thrombosis or a thrombophilia.

Findings from the Women's Health Initiative (WHI) randomised placebo-controlled trial (RCT) were published at the beginning of this century. They suggested that hormone replacement therapy (HRT) use increased the risk of cardiovascular disease and venous thromboembolism including pulmonary embolism and deep vein thrombosis The findings led to a decline in HRT prescriptions and negative publicity about the use of HRT for women with significant menopausal symptoms. Subsequent studies have shown that the risk of thrombosis with HRT relates to whether estrogen is combined with a progestogen and the route of administration of estrogen. In healthy women with no background medical problems, transdermal hormone replacement is not associated with an increased risk of thrombosis. However, much less is known about the safety of various HRT preparations in women with a high background risk of thrombosis. These cases can often be challenging for clinicians with uncertainties around testing for thrombophilia, use of anticoagulation and striking a balance between the risks and benefits of prescribing HRT. This article will review the mechanism of thrombosis with differing types of HRT and present the evidence from the relevant trials. The article will also present the evidence that specifically relates to women with a personal history of thrombosis or thrombophilia (heritable and acquired) to enable clinicians to better individualise the risk assessment for each woman requesting HRT and understand the role of thrombophilia screening or concomitant anticoagulation in such situations.

The effect of hormone replacement therapy on cognition and mood.

To summarise the available data regarding the effect of hormone replacement therapy (HRT) on cognition and mood in women. Complaints of impaired cognition and mood are common in the peri-menopausal and menopausal period. There is debate as to whether HRTcan ameliorate this phenomenon. A literature search of studies using electronic databases was conducted. Both randomised control trials and observational studies were included. Perimenopausal and menopausal women. Due to the heterogenicity of results it is challenging to draw firm conclusions. The preparations used in many of the studies are older regimes no longer routinely used clinically. The notion of a 'critical window' for HRT is compelling, suggesting HRT has a positive impact on cognition when administered in the peri-menopausal or early postmenopausal period but may have negative effects on cognition in the older, postmenopausal woman. The evidence would seem to suggest importance of hormonal replacement in woman undergoing a surgical menopause, especially when young. It remains unclear for how long they ought to continue HRT though until at least the natural age of the menopause seems reasonable. Evidence for a positive effect of HRT on mood is more convincing, though possibly more efficacious in the younger age group. The effect of HRT on anxiety is less clear. Further study, particularly focusing on the more contemporaneous HRT preparations, is warranted before evidence-based conclusions can be drawn.

Dietary restrictions – Ingredients and excipients in Hormone Replacement Therapy (HRT) products

Up to 20% of the UK population may have dietary restrictions due to ethical, lifestyle or religious views. It is important for clinicians to be aware of the constituents of what is prescribed, so that the patient can make an informed choice about their medication. This will improve both compliance and the therapeutic relationship. This article looks at the constituents of common HRT preparations currently available in the United Kingdom.

Effectiveness of transdermal oestradiol and natural micronised progesterone for menopausal symptoms.

This article discusses the role of hormone replacement therapy (HRT) in the management of menopausal symptoms, and specifically considers the advantages of different types and preparations of HRT, based on the current medical evidence. The menopause is a normal life event for women, not an illness or a medical condition. However, the effects of the menopause often have a negative impact on women’s wellbeing and quality of life. Furthermore, the low oestrogen levels and other biological changes that occur in these women are also associated with an increased risk of cardiovascular disease, osteoporosis, diabetes, and dementia. In addition to hot flushes and sweats, symptoms include mood changes, memory loss, urogenital atrophy, reduced libido, sleep disturbances, joint pains, and muscle stiffness.1 These symptoms can be non-existent, or can last for a few years or even decades. Much of the negative publicity surrounding HRT stems from misinterpretation by the media of the findings from the Women’s Health Initiative (WHI) study,2 published more than a decade ago. Many women and healthcare professionals are still unnecessarily concerned about the perceived risks of HRT, resulting in a significant proportion of women currently being refused HRT and often being inappropriately offered antidepressants. There is clear evidence to support that, …

The management of menopause in women with a history of endometriosis: a systematic review.

BACKGROUNDEndometriosis is typically regarded as a premenopausal disease, resolving after natural or iatrogenic menopause due to declining oestrogen levels. Nonetheless, case reports over the years have highlighted the incidence of recurrent postmenopausal endometriosis. It is now clear that both recurrence and malignant transformation of endometriotic foci can occur in the postmenopausal period. Postmenopausal women are commonly treated with hormone replacement therapy (HRT) to treat climacteric symptoms and prevent bone loss; however, HRT may reactivate endometriosis and stimulate malignant transformation in women with a history of endometriosis. Given the uncertain risks of initiating HRT, it is difficult to determine the best menopausal management for this group of women.OBJECTIVE AND RATIONALThe aim of this study was to systematically review the existing literature on management of menopausal symptoms in women with a history of endometriosis. We also aimed to evaluate the published literature on the risks associated with HRT in these women, and details regarding optimal formulations and timing (i.e. initiation and duration) of HRT.SEARCH METHODSFour electronic databases (MEDLINE via OVID, Embase via OVID, PsycINFO via OVID and CINAHL via EbscoHost) were searched from database inception until June 2016, using a combination of relevant controlled vocabulary terms and free-text terms related to ‘menopause’ and ‘endometriosis’. Inclusion criteria were: menopausal women with a history of endometriosis and menopausal treatment including HRT or other preparations. Case reports/series, observational studies and clinical trials were included. Narrative review articles, organizational guidelines and conference abstracts were excluded, as were studies that did not report on any form of menopausal management. Articles were assessed for risk of bias and quality using GRADE criteria.OUTCOMESWe present a synthesis of the existing case reports of endometriosis recurrence or malignant transformation in women undergoing treatment for menopausal symptoms. We highlight common presenting symptoms, potential risk factors and outcomes amongst the studies. Sparse high-quality evidence was identified, with few observational studies and only two randomized controlled trials. Given this paucity of data, no definitive conclusions can be drawn concerning risk.WIDER IMPLICATIONSDue to the lack of high-quality studies, it remains unclear how to advise women with a history of endometriosis regarding the management of menopausal symptoms. The absolute risk of disease recurrence and malignant transformation cannot be quantified, and the impact of HRT use on these outcomes is not known. Multicentre randomized trials or large observational studies are urgently needed to inform clinicians and patients alike.

Oral Contraceptives and HRT Risk of Thrombosis.

Estrogen-containing medication, prescribed either for contraception in women of reproductive age or for prevention of cardiovascular events and osteoporosis as well as for alleviation of symptoms related to menopause, is associated with changes in the hemostatic balance and contributes to increased risk of development of venous thromboembolic complications. This risk is dose and medication dependent, increases with age, congenital and/or acquired predisposition to thrombosis, and mode of administration. This review attempts to summarize the current knowledge regarding the pathophysiology of oral contraceptive (OC) and hormone replacement therapy (HRT) -induced prothrombotic state in women, the risk of thrombosis associated with administration of various commercially available OCs and HRT, the additional risk in women with hereditary or acquired thrombophilia, and the currently available recommendations regarding massive screening of women for thrombophilia prior to initial prescription or continuation of treatment with OCs and HRT preparations.

Migraine in perimenopausal women.

Hormonal changes during the reproductive cycle are thought to account for the variation in migraine occurrence and intensity. Although the majority of women and the specialists treating them do not consider migraine as a component of the climacteric syndrome, many women, in fact, do experience migraine during perimenopause. If a woman already suffers from migraine, the attacks often worsen during menopausal transition. Initial onset of the condition during this period is relatively rare. Women with the premenstrual syndrome (PMS) prior to entering menopause are more likely to experience, during late menopausal transition, an increased prevalence of migraine attacks. Hormone replacement therapy (HRT) can be initiated during the late premenopausal phase and the first years of postmenopause to relieve climacteric symptoms. The effect of HRT on migraine, either as a secondary effect of the therapy or as a preventive measure against perimenopausal migraine, has been variously investigated. HRT preparations should be administered continuously, without intervals, to prevent sudden estrogen deprivation and the migraine attacks that will ensue. Wide varieties of formulations, both systemic and topical, are available. Treatment with transdermal patches and estradiol-based gels is preferable to oral formulations as they maintain constant blood hormone levels. Natural menopause is associated with a lower incidence of migraine as compared with surgical menopause; data on the role of hysterectomy alone or associated with ovariectomy in changing the occurrence of migraine are till now unclear.

Postmenopausal vaginal bleeding in women using hormone replacement therapy

To estimate the risk of endometrial cancer in postmenopausal women presenting with vaginal bleeding using estrogen-progestogen hormone replacement therapy (HRT) regimens and to assess if the duration of HRT use has an effect on the risk of diagnosing endometrial cancer. Cross-sectional study of consecutive women presenting with postmenopausal vaginal bleeding at a gynaecological oncology centre in the UK. Main outcome measures Endometrial cancer diagnosis. Over a 62-month period, 4847 women were investigated for postmenopausal vaginal bleeding. The majority of women (4097, 84.5%) did not use any HRT preparation at the time of initial referral and 750 (15.5%) women were using combined HRT preparations. A total of 298 (6.1%) women were diagnosed with endometrial carcinoma. Women using HRT preparations were significantly less likely to be diagnosed with endometrial cancer compared with women not using HRT (adjusted odds ratio = 0.229, 95% CI 0.116-0.452; P < 0.0001). The longer duration of HRT use did increase the risk of diagnosing endometrial cancer in women presenting with postmenopausal vaginal bleeding, but this was not statistically significant. Postmenopausal women presenting with vaginal bleeding and using combined HRT preparations have significantly lower risk of being diagnosed with endometrial cancer when compared with women not using HRT.

Hypoglycaemia, phaeochromocytoma and features of acromegaly: a unifying diagnosis?

A 53-year-old school teacher was admitted to hospital for investigation of recurrent episodes of spontaneous hypoglycaemia after presenting to the emergency services with loss of consciousness and capillary blood glucose of 1.4 mmol/l. Past medical history was otherwise unremarkable, except for a 10-year history of problematic sweating. This had been treated by her general practitioner with various preparations of hormone replacement therapy (HRT) with little success. However, her symptoms had worsened over the preceding 3 months, associated with mild frontal headaches, but with no palpitations, flushing or pallor. She had also recently been found to be hypertensive and had noticed a change in her facial appearance, associated with increased shoe size, and an inability to wear her rings. Her hair had also recently become curly, having previously always been straight. Accordingly, her doctor had referred her to the endocrinology outpatient clinic for assessment of possible growth hormone excess, but she was unfortunately admitted with hypoglycaemia prior to her consultation. She drank only moderate amounts of alcohol, and had no access to oral antidiabetic agents or insulin. Current medication included HRT, lisinopril, omeprazole and simple analgesics only. There was no family history of endocrine disease. Examination revealed coarsening of facial features, especially the lips and nose, and multiple skin tags were present over the neck and upper back. Blood pressure was mildly elevated at 148/84 mmHg on admission, with no postural drop. There was no skin pigmentation and visual fields were normal to confrontation. Initial investigations including urea and electrolytes, calcium, full blood count and liver function tests were normal except for a raised alkaline phosphatase level of 120 U/l (normal range [NR]: 20–80). An oral glucose tolerance test was planned to assess for suppression of growth hormone, but this was not feasible due to frequent episodes of severe hypoglycaemia. However, insulin-like growth …

Effects of combined hormone replacement therapy or its effective agents on the IGF-1 pathway in skeletal muscle

Objectives To investigate the effects of combined hormone replacement therapy (HRT) and its effective agents on the IGF-1 signaling pathway. Design and methods To examine the effects of HRT on skeletal muscle in vivo, we utilized pre- and post-intervention samples from a randomized double blinded trial with 50–57-year-old women. The intervention included the year-long use of either HRT preparation (2 mg 17β-estradiol, E 2; 1 mg norethisterone acetate, NETA, n = 10) or placebo (CO, n = 9). Microarray technology and quantitative PCR (qPCR) were used to study the expression of insulin-like growth factor I ( IGF-1) and its splice variants as well as IGF-1 receptor, Akt1, mTOR, FOXO1, FOXO3, atrogin, estrogen receptors and androgen receptor in muscle samples. Serum concentrations of IGF-1, E 2 and testosterone were measured. C2C12 myotubes were fed with E 2 or NETA followed by analyzing the expression of essentially the same gene transcripts as in human samples by qPCR and phosphorylation of Akt and mTOR by Western blotting. Results The gene expression of IGF-1 and its splice variant, IGF-1Ec (also known as the mechano growth factor or MGF), mTOR, FOXO3, and AR was up-regulated among the HRT users compared to the CO (P < 0.05), while Akt1 was down-regulated (P < 0.05). The change in the level of IGF-1Ec transcript correlated positively with muscle size at post-intervention (r = 0.5, P < 0.05). In C2C12 myotubes, no statistically significant effects of either E 2 or NETA at the level of gene transcripts studied were identified. The amount of phosphorylated Akt appeared to respond to NETA, albeit the response was not statistically significant. Phosphorylation of mTOR did not respond to either of the treatments. Conclusion Year-long postmenopausal HRT was found to affect the expression of the genes along the IGF-1 signaling cascade reflecting the higher muscle mass compared to the CO women. By using cell culture model we were, however, unable to confirm the possible differential role of E 2 and NETA. It appears that the synchronous presence of both effective agents of the HRT or the presence of yet unidentified microenvironmental factors providing proper paracrine signals naturally existing in the intact muscle tissue is critical for appropriate signaling via sex steroid-IGF-1 axis to occur.

Compliance with estrogen hormone replacement therapy after oophorectomy: a prospective study

To quantify compliance with using estrogen-only hormone replacement therapy (HRT) up until the time of mean age of natural menopause in women undergoing either bilateral oophorectomy or removal of one remaining ovary at the time of hysterectomy for benign disease. Prospective study. Annual questionnaire follow-up for ten years of women undergoing hysterectomy and bilateral oophorectomy for benign disease aged 46 or less at the time of surgery. Gloucestershire Royal Hospital. Five hundred and twenty-one women recruited over a four-year period from 1994 to 1997. Compliance with HRT use, changes in HRT preparations and reasons for discontinuation. The median age of women at the time of hysterectomy was 42 (range 22-46) years; 4.9% (n = 24) stopped HRT within the first two years and 16.5% (n = 86) by the end of the study. The majority of women were prescribed HRT tablets (253, 48%) and the next most common being patches. In total, there were 1271 episodes of changing HRT, with the range between 0 and 18 changes per woman over the ten-year period. In all, 32% of changes were to a different route of HRT, 19% were to a different preparation of the same route, 18% were to an increased dose of the same preparation and 7% were to a decreased dose of the same preparation. Compliance with HRT use was high throughout the study, although responses decreased after five years. Change to HRT preparations was consistently high across all preparations. Women requiring HRT after surgical menopause need to be supported in finding the right preparation for them.

Colon cancer risk and different HRT formulations: a case-control study

BackgroundMost studies have found no increased risk of colon cancer associated with hormone replacement therapy (HRT), or even a decreased risk. But information about the effects of different HRT preparations is lacking.MethodsA case-control study was performed within Germany in collaboration with regional cancer registries and tumor centers. Up to 5 controls were matched to each case of colon cancer. Conditional logistic regression analysis was applied to estimate crude and adjusted odds ratios (OR) and 95% confidence intervals (95% CI). Stratified analyses were performed to get an impression of the risk associated with different estrogens and progestins.ResultsA total of 354 cases of colon cancer were compared with 1422 matched controls. The adjusted overall risk estimate for colon cancer (ColC) associated with ever-use of HRT was 0.97 (0.71 – 1.32). No clinically relevant trends for ColC risk were observed with increasing duration of HRT use, or increasing time since first or last HRT use in aggregate.Whereas the overall risk estimates were stable, the numbers in many of the sub-analyses of HRT preparation groups (estrogens and progestins) were too small for conclusions. Nevertheless, if the ColC risk estimates are taken at face value, most seemed to be reduced compared with never-use of HRT, but did not vary much across HRT formulation subgroups. In particular, no substantial difference in ColC risk was observed between HRT-containing conjugated equine estrogens (CEE) or medroxyprogesterone acetate (MPA) and other formulations more common in Europe.ConclusionEver-use of HRT was not associated with an increased risk of colon cancer. In contrary, most risk estimates pointed non-significantly toward a lower ColC risk in HRT ever user. They did not vary markedly among different HRT formulations (estrogens, progestins). However, the small numbers and the overlapping nature of the subgroups suggest cautious interpretation.

Hormone Replacement Therapy in Women with Epilepsy

To the Editors: Changes in reproductive hormone levels may influence seizure activity (Scharfman and MacLusky, 2006). A previous survey suggested that hormone replacement therapy (HRT) may adversely affect seizure control in women with epilepsy (Harden et al., 1999). Although this trial was terminated prematurely, resulting in greatly reduced statistical power, the results provide evidence that intake of estrogen/medroxyprogesterone acetate HRT in postmenopausal women with epilepsy is associated with some worsening in seizure control. A more recent study by Harden and colleagues (Harden et al., 2006) confirms the results of their previous survey (Harden et al., 1999), and raises a number of interesting points for discussion: Although HRT was widely used at the time the trial was initiated, intriguing ethical issues exist in conducting a placebo-controlled study to test the hypothesis that active treatment could cause seizure aggravation. One may argue, however, that based on evidence available at the time, HRT might have been a safe option in the enrolled population. Because an adverse influence on seizure control was confirmed, the question arises, what HRT component was responsible for the effect? The bulk of the evidence points to estrogens, which can have a facilitating effect on seizure activity (Logothetis et al., 1959; Logothetis and Harner, 1960; Hom and Buterbaugh, 1986; McEwen, 2002), although evidence on this is not univocal (Scharfman and MacLusky, 2006). Whether medroxyprogesterone acetate contributed to seizure deterioration is unknown. The authors elected to test the HRT preparation most widely prescribed in the United States. However, it might have been preferable in this population to combine estrogens with natural progesterone. Natural progesterone is converted to neuroactive metabolites, such as allopregnanolone, which have anticonvulsant activity in animal models by acting as positive allosteric modulators at the GABAA receptor (Kokate et al., 1994; Herzog, 1995; Reddy, 2001; Lonsdale and Burnham, 2003; Scharfman and MacLusky, 2006). Preliminary evidence suggests a positive effect of progesterone in catamenial epilepsy (Herzog, 1995, 1999). Whether use of natural progesterone instead of MPA would be a safer option for HRT is unknown. From a practical point of view, the relevance of this study has been reduced by the drastic decline in the use of HRT in postmenopausal women, after publication of the WHI results (Rossouw et al., 2002). Today, HRT is no longer recommended as preventive treatment in asymptomatic women, because the increased risks of breast cancer, coronary heart disease, stroke, and pulmonary embolism clearly outweigh any benefits. The authors are correct in pointing out that their results should not be interpreted as contraindicating the use of HRT for short-term control of postmenopausal symptoms in women with epilepsy. Their results do suggest, however, that the HRT regimen tested may not be the optimal one to use in these women. An interesting ancillary observation was that serum lamotrigine (LTG) levels decreased after initiation of HRT in both women who were treated with this drug. Although exclusion of these women from the analysis did not alter the results, these findings confirm previous reports that serum LTG levels can be reduced to a clinically significant extent by estrogen-containing preparations, including oral contraceptives (Sabers, 2003; Reimers et al., 2005; Sidhu et al., 2006). Careful clinical observation and, if possible, monitoring of serum LTG levels are recommended whenever estrogen-containing preparations are started or discontinued in women taking LTG.

Identifying Women at High Risk of Venous Thrombosis before Administration of Hormone Therapy

Over 100 million women worldwide use hormone therapy (HT), that is, oral contraceptives (OCs) or hormone replacement therapy (HRT); however, the use of HT is associated with an increased risk of venous thromboembolism (VTE), including deep-vein thrombosis, pulmonary embolism and cerebral vein thrombosis [1–3]. While the risk is low in absolute terms, OCs are the major cause of thrombotic events in young women [1]. The increased risk of VTE is most probably due to the administration of exogenous estrogens, which leads to procoagulant changes [1,2]. The risk is still present with low-dose OCs (second and third generations; 20–30 mg of the estrogen ethinylestradiol) used currently, and with HRT preparations, which contain even lower dosages of estrogen and progestin compared with OC. HRT increases the risk of VTE by 2–3-fold compared with women without HT [4]. The risk is higher during the first year of HT use (up to 1/1000/year), with the use of a third-generation OC (desogestrel or gestodene instead of levonorgestrel or norgestrel) and among women with thrombophilic risk factors [1].

A one-year randomized double-blind, multicentre study to evaluate the effects of an oestrogen-reduced, continuous combined hormone replacement therapy preparation containing 1 mg oestradiol valerate and 2 mg dienogest on metabolism in postmenopausal women

Objectives To evaluate the impact of an oestrogen-reduced, continuous combined hormone replacement therapy preparation containing 1 mg oestradiol valerate (1EV) and 2 mg dienogest (2DNG) on metabolism.Methods In a randomized double-blind study, 1EV/2DNG was compared with a reference preparation containing 1 mg 17ß-oestradiol and 0.5 mg norethisterone acetate (E2/NETA). For the primary variable, i.e. the ratio of HDL cholesterol (week 52 to baseline), at least 98 case evaluations were planned. Secondary variables were other lipid parameters, haemostasis factors and carbohydrate metabolism.Results After 1 year of treatment, the mean HDL cholesterol levels had decreased by 4.5 ± 14.8% in the 1EV/2DNG group and by 6.1 ± 13.9% in the E2/NETA group (treatment difference NS). The ratio of HDL cholesterol (week 52 to baseline) was 0.944 for 1EV/2DNG and 0.929 for E2/NETA (geometric means). The primary efficacy variable, the ratio of the geometric means of the two treatments (1EV/2DNG/E2/NETA) was 1.016, with a lower one-sided 95% confidence limit of 0.973, which was clearly above the prespecified non-inferiority bound of 0.85 (p-value < 0.001). HDL2 cholesterol increased by 0.3 ± 34.4% (1EV/2DNG) and decreased by 6.2 ± 34.3% (E2/NETA; treatment difference NS); HDL3 cholesterol decreased by 4.4 ± 19.9% (1EV/2DNG) and 8.2 ± 17.7% (E2/NETA; treatment difference NS). Changes in the haemostasis and carbohydrate variables were very similar in both treatment groups.Conclusion This study provides evidence that a new oestrogen-reduced HRT preparation containing 1 mg oestradiol valerate and 2 mg dienogest has no major impact on lipid variables. Minimal changes were seen in haemostatic and carbohydrate variables.

Use of hormone replacement therapy before and after ovarian cancer diagnosis and ovarian cancer survival

Use of hormone replacement therapy (HRT) has been hypothesized to affect survival of epithelial ovarian cancer (EOC). We studied 5-year survival in patients with invasive EOC and borderline ovarian tumors (BOT) according to HRT use before and after diagnosis in a prospective nation-wide cohort study of 799 women diagnosed with EOC (n = 649) and BOT (n = 150) aged 50-74 years in 1993-1995 in Sweden. Cox regression was used to obtain multivariate age-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). Multivariate models included indicator variables for age, tumor stage, grade and histological subtype. After 5 years of follow-up, 45% of the patients with EOC and 93% of the patients with BOT were alive. For women with BOT there were no associations between HRT-use pre- or postdiagnosis and survival. There was no overall difference in 5-year EOC survival according to use HRT before diagnosis (multivariate HR = 0.83, 95% CI = 0.65-1.08), except for serous EOC (HR = 0.69, 95% CI = 0.48-0.98). Analyses of different HRT preparations, duration and recency of use did not reveal any variations in pattern of survival. We observed a better survival for EOC-patients who used HRT after diagnosis (multivariate HR = 0.57, 95% CI = 0.42-0.78). We conclude that HRT-use prior to diagnosis of EOC does not affect 5-year survival, except for a possible survival advantage in serous EOC. Women using HRT after diagnosis had a better survival than women with no use, but we cannot rule out that this latter finding may reflect a subtle selection process.