Safety and benefit considerations for menopausal hormone therapy

Introduction: While benefits and risks of hormone therapy (HT) have been shown in rigorous randomized, controlled trials, clinical use and further study have discovered effects of age, time of HT initiation, and differential effects of various regimens and administration routes on its safety profile.

Areas covered: The safety of HT with regard to cardiovascular disease, thrombosis, the endometrium, the breast, and cognition was reviewed. Differential safety effects of estradiol versus conjugated equine estrogens, and progesterone versus synthetic progestins are reported.

Expert opinion: Perceived safety of HT has evolved based on data from observational studies, the Women’s Health Initiative and its subsequent analyses, more recent randomized, controlled trials, and studies examining the differences between different estrogens and between different progestogens. Unexpected safety concerns with HT became apparent with release of the first results from WHI. Differences between estrogen-alone versus estrogen-progestogen therapies, estradiol versus conjugated equine estrogens, and progesterone versus progestins were found in subsequent WHI analyses and studies examining components of various regimens. The decision to use HT depends on balancing risks and benefits for each individual and determining the most appropriate choice of therapy, dosing, and route of administration, while also considering the safety evidence of different estrogens and progestogens.     

Dienogest-induced major depressive disorder with suicidal ideation: A case report

Rationale:Dienogest is a type of progestin used for the treatment of endometriosis (EM). However, a significant adverse effect of dienogest is depression; therefore, assessing for a history of mood disorders is recommended before prescribing the drug. Herein, we present the case of a patient with no history of psychiatric disorders who was diagnosed with dienogest-induced major depressive disorder. This case emphasizes the importance of close monitoring for negative mood changes in patients taking dienogest.Patient concerns:A 41-year-old woman underwent surgery for EM. Postoperatively, her gynecologist prescribed dienogest (2 mg/d) to control EM symptoms. Two months after the initiation of dienogest, she manifested insomnia almost daily, gradually became depressed, lost interest in all activities, had incessant cries, and repeatedly thought of death. She had no history of major physical or psychiatric disorders.Diagnosis:Major depressive disorder, single episode, severe.Interventions:A psychiatric consultation was recommended, an antidepressant was prescribed, and dienogest was discontinued.Outcomes:Two weeks later, there was significant improvement in the symptoms, and after 4 weeks, she remained in a stable mood with no suicidal thoughts. She was followed up for 13 months with a maintenance dose of escitalopram (5 −10mg/d), until the psychiatrist recommended treatment discontinuation, with a confirmed state of remission.Lessons:This was a case of dienogest-induced depression in a patient with no history of mood disorders. Clinicians should be aware of the possibility of the occurrence of severe depression in progestin users regardless of their previous history.     

Hormone therapy modulates ETA mRNA expression in the aorta of ovariectomised New Zealand White rabbits

Objective. To study the effect of 17β-estradiol (E₂) or conjugated equine estrogens (CEE) alone and in combination with norethisterone acetate (NETA) or medroxyprogesterone acetate (MPA) on the endothelin-1 (ET-1) system.

Methods. New Zealand White rabbits were treated with E₂, CEE, E₂ + NETA, CEE + MPA or placebo. The thoracic aorta and the epicardial coronary artery were used for mRNA expression and myograph analyses, respectively.

Results. E₂ and CEE alone significantly reduced ET-1 receptor subtype A (ET_A) mRNA expression compared with placebo treatment. The E₂-induced reduction in ET_A mRNA expression persisted with the co-administration of NETA, but the CEE induced reduction in ET_A mRNA expression was not maintained with the co-administration of MPA. Treatment with CEE alone significantly increased endotelin-1 converting enzyme (ECE) mRNA expression and CEE combined with MPA reduced prepro-endothelin-1 (ppET-1) mRNA expression when compared with placebo. ET-1 receptor subtype B mRNA expression and ET-1 induced vasocontraction was unaffected by treatment.

Conclusions. E₂ and CEE treatment exert potentially beneficial vascular effects through regulation of the ET_A receptor. The effect was maintained with the co-administration of NETA, but not MPA. The differential effects of specific hormone components may explain the variable effects of hormone therapy on the arterial wall.     

Effects of genotype on differential behavioral responsiveness to progesterone and 5α-dihydroprogesterone in mice

Thirty female CD-1 mice, 30 female Swiss-Webster mice, 45 hybrid female mice of the strain SWCD1F ₁ , and 45 hybrid female mice of the strain CD1SWF ₁ were ovariectomized and administered estradiol benzoate once weekly for 6 weeks. Estrogen injections were followed 2 days later by injections of progesterone, dihydroprogesterone (DHP), or oil and the animals were tested for receptivity 7 hr later. Over the six tests, there was a progressive increase in the frequency of lordosis responses in all strains following progesterone treatment. However, lordosis scores varied widely across animals within strains. Following DHP treatment, lordosis frequency was not increased in the Swiss-Webster strain. Females in the other strains did show a progressive increase in lordosis frequency over weeks. The data indicate that the hybrid strains develop the potential to respond to DHP and thus behave like the CD-1 strain, suggesting that sensitivity to DHP is a dominant trait.Supported by Grant HD-00893 to R. E. W. from the National Institute of Child Health and Human Development.     

Pharmacodynamics of combined estrogen-progestin oral contraceptives: 2. effects on hemostasis

Introduction: The pharmacodynamic effects of various combined oral estrogen-progestin combinations (COC) are examined for their components alone or in the various combined formulations. Special emphasis is given to products containing natural estrogens.

Areas covered: Recent information on the effect of androgens, estrogens, progestins, as well as various COC combinations on the coagulation cascade will be reviewed aiming at providing an updated picture.

The present article reviews hemostatic changes occurring during use of classic and modern combinations of estrogens (ethinyl estradiol, estradiol, estradiol valerate and estetrol) and new progestins (desogestrel, gestodene, dienogest, drospirenone, nomegestrol acetate), compared to classic compounds, such as levonorgestrel.

Both pro- and anti-coagulatory effects of COC in healthy women are detailed and possible links with incidence of thromboembolic events are discussed.

Expert commentary: Overall, the picture is reassuring: the use of natural estrogens and of new generation progestins has reduced pro-coagulatory changes in healthy subjects, although the observed differences in the risk of venous thromboembolism between second and third generation progestins is still incompletely understood. At the same time, there still is a need for large comparative and surveillance studies before firm conclusions can be drawn.

At any rate, available evidence indicates that hemostatic effects of the newer COC, especially those utilizing natural estrogens, are minimal and often remain with the normal range.     

Expression of 67 kDa laminin receptor in human breast cancer cells: regulation by progestins

The level of 67 kDa laminin receptor (67LR) expression on breast and colon tumor cell surfaces was previously shown to be correlated with the capacity of tumor cells to metastasize. In the present work we investigate the effects of progestins and estrogen on the expression of 67LR in two sublines of the T47D human breast cancer cells: weakly tumorigenic, poorly invasive parental T47D cells and a highly tumorigenic, more invasive T47Dco subclone. Inmmunoblotting with an affinity purified antibody directed against a synthetic peptide recognizes the 67LR in these cells. 67LR expression in the T47Dco subclone is 5,5-fold higher than in their parental T47D cells. Treatment of T47D cells with 1 nM of the synthetic progestin R5020 results in a 4-fold increase in 67LR protein expression. Estrogen also induced 67LR expression, but only by 1.5-fold. The progestin-stimulated expression of the 67LR correlates with a 4.3-fold increase in attachment of T47D cells to laminin. A monoclonal antibody, mAb 13, directed against ₁ integrin, completely blocks the attachment of T47D cells to fibronectin, only partially inhibits the attachment of T47D cells to laminin, and appears not to affect the progestin-stimulated laminin attachment of T47D cells. A new antiprogestin, ZK 112.993, significantly inhibits both progestin-stimulated 67LR expression and the increased attachment to laminin. These results suggest a possible role for progestin in mediating one of the multiple events thought to be important in metastasis of steroid receptor positive human breast cancer cells.     

Bcl-2,ER,PR,C-erbB-2在乳腺癌组织中的表达及意义

[目的]探讨乳腺癌组织中Bcl-2,ER,PR,C-erbB-2的表达情况及其与生物学行为及预后的关系.[方法]采用免疫组织化学SP法检测131例乳腺癌组织中的Bcl-2,ER,PR,C-erbB-2的表达情况. [结果]在131例乳腺癌组织中Bcl-2,ER,PR,C-erbB-2的阳性表达率分别为84.7%,50.4%,58.8%, 46.6%,Bcl-2蛋白表达与ER,PR表达呈显著正相关,C-erbB-2蛋白表达与淋巴结转移情况无相关性. Bcl-2蛋白在浸润性导管癌和原位癌中的阳性表达率相近,在髓样癌中表达率较低.ER,PR在原位癌、浸润性导管癌和髓样癌中阳性表达率分别为76.9%,59.8%,21.4%,相比较均有显著性差异.C-erbB-2蛋白在原位癌、浸润性导管癌和髓样癌中阳性表达率分别为61.5%,45.7%,35.7%,相比较均有显著性差异.在Bcl-2阴性表达的乳腺癌组织中C-erbB-2蛋白的表达与ER,PR表达呈负相关.[结论]联合检测乳腺癌组织中Bcl-2,ER,PR,C-erbB-2的表达情况,有利于评估乳腺癌的生物学行为及预后,同时对术后个体化学治疗方案的制定亦有参考价值.     

早期子宫内膜癌保留生育功能的治疗

手术治疗仍是治疗子宫内膜癌（包括重度不典型增生）的标准方法。虽然可取得良好的治疗效果,但术后患者会丧失生育能力,这会对患者的生存质量和社会-心理状态造成严重影响。该文以近期FIGO肿瘤报告和NCCN最新版指南为基础,总结了子宫内膜癌保留生育功能治疗方法的进展和我院的治疗经验。     

Bioactive 5-Reduced 16α,17α-Cyclohexanoprogesterone Derivatives Weakly Interact with Proteins of the Soluble Uterine Fraction

We studied competitive activities of 16,17-cyclohexano-5- and 5-dihydroprogesterone in replacing ₃H-progesterone and ₃H-16,17-cyclohexano-6-methylprogesterone from protein complexes. Direct binding of ₃H-5-reduced derivatives with proteins of soluble fractions from rat and rabbit uteri was also assayed. Cd values for 5-reduced derivatives were in the micro- or submicromolar range. The data suggest that biological effects of these analogues are not mediated via soluble uterine receptors.