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Open Access
Full open access to this and thousands of other papers at Abnormal Bleeding During Menopause Hormone Therapy:
Insights for clinical Management
Sebastião Freitas de Medeiros1,2, Márcia Marly Winck Yamamoto2 and Jacklyne Silva Barbosa21Department of Gynecology and Obstetrics, Medical Science School, Federal University of Mato Grosso (UFMT), Cuiabá, Mato Grosso, Brazil. 2Tropical Institute of Medicine Reproductive and Menopause, Cuiabá, Mato Grosso, Brazil. Objective: Our objective was to review the involved mechanisms and propose actions for controlling/treating abnormal uterine bleed-
ing during climacteric hormone therapy.
Methods: A systemic search of the databases SciELO, MEDLINE, and Pubmed was performed for identifying relevant publications on
normal endometrial bleeding, abnormal uterine bleeding, and hormone therapy bleeding.
Results: Before starting hormone therapy, it is essential to exclude any abnormal organic condition, identify women at higher risk for
bleeding, and adapt the regimen to suit eachwoman's characteristics. Abnormal bleeding with progesterone/progestogen only, combined sequential, or combined continuous regimens may be corrected by changing the progestogen, adjusting the progestogen or estrogen/ progestogen doses, or even switching the initial regimen to other formulation.
Conclusion: To diminish the occurrence of abnormal bleeding during hormone therapy (HT), it is important to tailor the regimen to the
needs of individual women and identify those with higher risk of bleeding. The use of new agents as adjuvant therapies for decreasing abnormal bleeding in women on HT awaits future studies.
Keywords: hormone therapy, climacteric, menopause, abnormal uterine bleeding, endometrium
Clinical Medicine Insights: Women's Health 2013:6 13–24 This article is available from .
the author(s), publisher and licensee Libertas Academica Ltd.
This is an open access article. Unrestricted non-commercial use is permitted provided the original work is properly cited.
Clinical Medicine Insights: Women's Health 2013:6 de Medeiros et al Hormone therapy (HT) is the most effective method The review, structured in sections, was developed after for relieving the effects of hypoestrogenism follow- a detailed analysis of the publications found on sched- ing menopause, particularly vasomotor symptoms with uled or unscheduled abnormal bleeding in menopause high prevalence in different populations.1–3 Despite women receiving HT via different administration the benefit of the HT, unscheduled/unwanted bleeding routes, doses, and regimens. The main objective was decreases patients' compliance with long-term use.4,5 to provide recommendations for the management of Though abnormal bleeding is the main cause for HT women with abnormal bleeding on hormone therapy. discontinuation, there are no established guidelines The databases SciELO, MEDLINE, and Pubmed for preventing or treating it during HT in climacteric were searched to identify the most relevant publica- women. Few studies have been published on this sub- tions over the last few years. This database search ject6–9 likelybecause the knowledge of the exact mech- was expanded through a search for and review of anisms of bleeding use of different regimens remains bibliographic citations in the articles consulted. If the limited.10,11 In the absence of clinical guidelines, the citations provided essential knowledge, older articles objectives of this review are (1) to propose actions to were also included. Only articles or reviews published treat bleeding in combined sequential regimens based in journals with an editorial board were examined. on current knowledge of mechanisms that trigger the Studies were limited to levels of evidence 1 to 3 and onset of bleeding and assure endometrial repair, and (2) degrees of recommendation/strength of evidence from to propose actions to correct breakthrough bleeding that A to C. Therefore, the best available research evidence occurs with combined continuous regimens regardless was used to develop some of the recommendations. of the duration of use. According to the current clas- Keywords included in the search were hormone ther- sification of the causes of abnormal uterine bleeding, apy, menopause, climacteric, abnormal uterine bleed- the bleeding that occurs with the use of sex steroids is ing, dysfunctional uterine bleeding, endometrium, defined as iatrogenic,12 and this review considers the sex steroids, and menstrual bleeding.
definitions of spotting/bleeding occurring with com- bined hormonal contraceptives for defining spotting/ Steroid preparation for hormone therapy bleeding occurring in combined HT (Table 1).
Even though the endometrial response is highly variable with different preparations, regimens, and women's ages, an estrogen/progestogen balance Table 1. Proposed definitions of different types of bleeding
should be individualized to assure the protec- during hormone therapy.* tive effect of the endometrium and avoid abnormal bleeding. Concerning the estrogen component, 2 mg Any scheduled or unscheduled bleeding requiring more of estradiol valerate, 1 to 2 mg of oral 17β-estradiol, than one sanitary napkin/day, during the use of any oral 0.625 mg of oral conjugated estrogen, and 50 µg of or non oral HT regimen.
estradiol transdermally are the recommended stan- Any scheduled or unscheduled bleeding not requiring dard daily doses. Nevertheless, it must be taken into any sanitary towel, or not more than one per day, account that the estrogen dose by itself may influence during the use of any oral or non oral HT regimen.
the incidence of irregular bleeding.9,11 A variety of pro- • Unscheduled bleeding/spotting gestogens are used combined with estrogens in HT. Any bleeding or spotting before the end of the As some of these progestogens may cause unwanted progestogen sequence in combined sequential regimen • Scheduled, programmed bleeding/spotting metabolic effects or negate the beneficial effects of Any bleeding or spotting occurring after the end of the estrogen, the choice of progestogen type, dose, route, progestogen sequence, in the combined sequential and the number of days of its administration should be based on a consideration of adverse effects and • early scheduled bleeding/spotting Any bleeding or spotting with onset before the end of endometrial impact.13 There is little information con- the progestogen sequence, in the combined sequential cerning how to choose a progestin for a particular patient, but the progestin's androgenic and metabolic *Adapted from reference 12.
properties and the impact on the endometrium should Clinical Medicine Insights: Women's Health 2013:6 HT bleeding management be considered.14 The recommended progestogen responses to the same regimens among individu- doses for endometrial protection in HT are shown in als, however. Concerning the type of progestogen, it Table 2. Considering the type of progestogen, it seems appears that levonorgestrel, desogestrel, and medroxy- that endometrium hyperplasia is more prevalent with progesterone acetate when given in low doses do not regimens containing levonorgestrel or medroxypro- reduce the estrogen receptors, but the expression of gesterone acetate (MPA) than those containing nore- progesterone receptor density may suffer significant thisterone acetate.11,15,16 The cyclic combination of alterations with the different regimens of HT.21 2 mg of 17-beta-estradiol and 10 mg of dydrogesterone It seems there is no significant increase in the endo- offers adequate endometrial protection even if given metrial vascular density in patients using HT when for three years.17 Conjugated estrogen 0.625 mg asso- compared with nonusers, but in HT users, the endome- ciated with 2.5 mg of medroxyprogesterone acetate trial vessels are fragile and have only endothelial cells, also assures endometrium protection for three years basal lamina, and pericytes to support their structure and of use.18 When these estrogens were associated with lack the muscle cells responsible for vasoconstriction.22 5 mg of MPA, the positive result was a decrease in In the endometrium, HT seems not to determine signif- bleeding intensity.19 icant increases in stromal vascular caliber, alteration in the expression of Matrix metalloproteinases (MMP), Endometrial modifications with hormone or increases in the vascular endothelium growth fac- tor (VEGF) production.22,23 However, the different pro- In the abnormal menstrual cycle, the diameter and gestins used in HT preparations may alter the balance total glandular area of the endometrium are greater between angiogenic promoters (VEGF) and inhibitors than those seen in the normal cycle even though the (thrombospondin-1).23 Despite the HT regimen, either stromal cellularity remains unaltered in the luteal combined sequential or continuous, endothelial cells phase. If the progestogen dose is unbalanced or high are found spread among the vessels and extravascular in any HT regimen, the result is small total area and tissues.24 With the combined continuous regimen, there glandular diameter, lower height of the glandular epi- is a reduction in smooth muscle actin in the vascular thelium, reduced glandular secretion, a lower number wall and pericytes and greater leukocyte invasion, of microvessels, and a higher number of dilated explaining the greater endometrial vascular fragility in venules. All of these modifications facilitate abnormal users of this regimen. In fact, some studies have shown bleeding.20 Therefore, in HT, the progestogen dose that leukocyte invasion, expression of metalloprotei- should be high enough to inhibit glandular cell divi- nases (MPs), and their tissue Inhibitor of metallopro- sion without causing secretory modifications. It must teinases (TIMPs) may be altered in the endometrium of be considered that there are different endometrial HT users, mainly during the bleeding episode.25 With this regimen, increased endometrial stromal prolifera- tion, alteration in endometrial integrity, remodeling, Table 2. Standard progestogen doses commonly used in
climacteric hormone therapy.
and repair also occur as a consequence of the increased endometrial microvascularization associated with the progestogen dose (mg)
higher activity of local enzymes, growth factors, and sequential
combined
other regulatory molecules.21,23,25 continuous
12–14 days/month regimen
Histological aspects of the endometrium under the influence of hormone therapy Atrophic, inactive, proliferative, early secretory, late secretory, and hyperplasic endometria have been reported in HT users of different regimens. Endometrial biopsies have been performed both in the absence of and during bleeding episodes.17 Comparison of the Cyproterone acetate biopsies found in bleeding patients with those per- formed in patients with no bleeding, under the same Clinical Medicine Insights: Women's Health 2013:6 de Medeiros et al regimens of HT, have not shown different results.26 The type of bleeding may or may not be related In those patients with abnormal bleeding, biop- to the histology, dose, and type of estrogen and pro- sies have shown atrophic (12.5%–44%), prolifera- gestogen used or to an imbalance between these two tive (6%–35%), hyperplastic (3%–19%), secretory steroids.37 Exogenous estrogens, both natural and (8%–16%), carcinomatous (1%–2%), hyperplastic synthetic, with doses used in HT, have practically the associated with cancer (11%), and dysfunctional same endometrial impact as endogenous estrogens. abortive (1%–2%)8,21 endometria.
However, exogenous progestogens are more potent In general, partial or complete secretory transfor- than progesterone, and, generally, they induce prema- mation occurs in most patients receiving the com- ture atrophy in the glandular epithelium and stromal bined sequential regimen,15,26 and biopsies performed cell decidualization.13 In case of an excess in the pro- during the progesterone phase have shown endome- gestogen component in a certain formula, an increased tria weakly secretory, secretory (40%–48%), prolif- 17-hydroxysteroid dehydrogenase activity may pro- erative (5.5%–36%), inactive (7%–40%), atrophic mote greater conversion of estradiol into estrone and (7%–25%), dysfunctional (1%–2%), or hyperplastic increased endometrial vascular fragility.35,38 (5%–8%).21–30 In the users of the combined continuous Little attention has been paid to the vascular and regimen, biopsies have shown endometria atrophic in molecular mechanisms underlying breakthrough 26% to 69%, proliferative in 13%, dysfunctional in bleeding in users of the combined continuous regimen, 5%, or hyperplastic in 2% to 5%.31 Nevertheless, add- but, under this regimen, there is little formation of spi- ing the results of biopsies with atrophic endometrium ral arterioles and endothelins,11,23 and breakthrough plus those with insufficient material for analysis, bleeding seems to occur as a result of atypical micro- the percentage increases up to 90% of cases.32 The vascularization formed, enzymatic vascular alteration, presence of endometrial polyp or other endometrial and impaired hemostatic mechanisms.11,23 Because the pathology have been reported in 7% to 8% of cases, microvascularization has only endothelial cells and the regardless of which regimen is used.27,33 basal membrane is poor in laminin, proteoglycans, and pericytes, there is greater vascular fragility, facilitating Mechanisms of abnormal bleeding the appearance of bleeding in the first months of HT. during hormone therapy In addition, the bleeding by itself can stimulate local The mechanisms involved in endometrial bleeding release of regulatory molecules (MMPs, interleukins, during HT are poorly understood. While normal men- and growth factors) and compromise the integrity, strual bleeding is universal and involves two-thirds remodeling, and repair of the microvascularization.23,25 of the endometrium, the bleeding that occurs during With continued and more prolonged use, the normal HT is focal and involves only the upper layer of the structure of the basal membrane of the endometrial endometrium. As a result of this difference, unwanted, vessels is restored, reducing the likelihood of break- unpredictable, intermittent, and, at times, prolonged through bleeding in the following months.39 bleeding are common occurrences in women on HT. In the combined sequential HT regimen, with con- Unlike what happens during menstruation, when tinuous estrogen and cyclic progestogen, withdrawal bleeding is mainly the result of the spiral arterioles bleeding should occur at the end of the progestogen rupture,34 bleeding during HT comes from damaged sequence and present the characteristics of normal newer microvascular capillaries developed in the menstrual bleeding.17 With this regimen, the expected endometrium.35 Abnormal bleeding does not occur in normal bleeding should occur only after the 10th day all women on HT, and the reason for this is unknown, of progestogen, when administered orally15,40 or after but in those with bleeding, the bleeding may be asso- the 8th or 9th day, when administered transdermally.41 ciated with endometrial changes already mentioned: If the estrogen dose is insufficient in relation to the higher stromal expression of growth factors, alteration action of the progestogen in the formula used, normal in the synthesis of MMP and its TIMPs, increased pro- bleeding may occur for 4 to 5 days after the end of liferation of the endothelium vascular, reduced prolif- the progestogen sequence, and endometrial healing eration and differentiation of the musculature of spiral may be delayed, translated by persistent spotting at arterioles, and reduced endothelin expression.25,36 the end of the bleeding period. On the other hand, if Clinical Medicine Insights: Women's Health 2013:6 HT bleeding management the progestogen dose is insufficient, early sloughing Table 3. Occurrence of abnormal bleeding with different
of the endometrium may start before the end of the hormone preparations used in the combined sequential sequence of progestogen tablets, and this bleeding may persist in small amounts for several days before Abnormal bleeding References
increasing; the result may be a prolonged flow.35,40,42 in the first year (%)
Prevalence of abnormal bleeding during Both combined sequential and continuous HT regi- mens were developed to result in the patient having predictable bleeding or to have no bleeding at all.43 In clinical practice, the prevalence of abnormal bleed- ing in HT users will depend on myometrial integrity, endometrium thickness, whether the woman is in the premenopause or postmenopause period at the start of replacement therapy, the time that has elapsed since menopause, the pattern of bleeding before meno- pause, the dose and type of sex steroids, the regimen used, and the treatment duration.31,44–49 In the sequential regimen, irregular bleeding is expected to occur in 8% to 40% of users (Table 3). More than half of users of this regimen may bleed before day 11 of the progestogen sequence, and less than 10% of women may experience recurrent episodes of break- through bleeding.50 On the other hand, the percentage of women with abnormal bleeding on the combined continuous regimen, either oral or transdermal, ranges from, 0% to 77% in the first few years of treatment (Table 4).44,51–54 With this continuous regimen, the per- Abbreviations: MG, medrogestone; NMG, nomegestrel acetate;
TMG, trimegestone; MPA, medroxyprogesterone acetate; DHG, centage of women with bleeding decreases after 6 to dydrogesterone; P4, progesterone; Cee, conjugated equine estrogen; 12 months of use, and after 9 months, it is expected that ev, valerate estradiol; e2, 17β-estradiol.
only 3% to 10% will still present this complication.32,45,55 In the transdermal route, the percentage of women who norethisterone (12% vs. 26%, respectively).19 When still present bleeding or spotting after 12 months of use the years postmenopause are considered, it seems that ranges from 10% to 20%.56 the longer the time period after menopause that HT is It must be always considered that both regimen and started, the less prevalent is abnormal bleeding.19,61 estrogen dose are important factors in the occurence of abnormal bleeding.31,53,57,58 With the continuous com- Causes of abnormal bleeding during bined regimen with the lower dose of estrogen, bleed- ing occurs in around 20% of users, and when higher The most common causes of abnormal bleed- doses are used, bleeding may occur in up to 43% of ing during climacteric HT are poor compliance, users.19,59 Besides the estrogen dose, the types of estro- the incorrect use of steroids, concomitant use of gen and progestogen used also seem to be relevant in some broad-spectrum antibiotics, forgetting to inducing bleeding.14,31,60 Information on this aspect is take the HT tablets, alterations in absorption or very limited, but endometria exposed to conjugated metabolism/excretion of hormones, lack of syn- estrogens associated with medroxyprogesterone chronization between endogenous and exogenous appear to be more vulnerable to bleeding than endo- hormones in the perimenopausal users, endometrial metria exposed to the association of estradiol and exposure to an unbalanced percentage/quantity of Clinical Medicine Insights: Women's Health 2013:6 de Medeiros et al Table 4. Occurrence of abnormal bleeding with different hormone preparation used in the combined continuous HT regimen.
compound
Abnormal bleeding in the first year (%)
0.625 mg Cee plus 2.5 mg MPA 0.625 mg Cee plus 5.0 mg MPA 0.450 mg Cee plus 1.5 mg MPA 0.450 mg Cee plus 2.5 mg MPA 2.0 mg e2 plus 5.0 mg MPA 1.0 mg e2 plus 2.5 mg MPA 2.0 mg ev plus 0.7 mg NeTA 0.625 mg Cee plus 2.5 mg NeTA 0.450 mg Cee plus 2.5 mg NeTA 0.450 mg Cee plus 1.5 mg NeTA 0.300 mg Cee plus 0.15 mg NeTA 0.625 mg Cee plus 0.7 mg NeTA 1 mg e2 plus 0.1 mg NeTA 1 mg e2 plus 0.25 mg NeTA 1 mg e2 plus 0.5 mg NeTA 2 mg e2 plus 1.0 mg NeTA 1 mg e2 plus 0.1 mg NeTA 1 mg e2 plus 0.25 mg NeTA 1 mg e2 plus 0.5 mg NeTA 0.5 mg e2 plus 1.0 mg NeTA 0.5 mg e2 plus 0.5 mg NeTA 1.0 mg e2 plus 0.25 mg NeTA 1.0 mg e2 plus 3.0 mg DRSP 2.0 mg e2 plus 2.0 mg DRSP 1.0 mg e2 plus 1.0 mg DRSP 1.0 mg e2 plus 0.5 mg DRSP 2.0 mg e2 plus 15 mg DHG 2.0 mg e2 plus 10 mg DHG 62 (all combination) 2.0 mg e2 plus 5.0 mg DHG 2.0 mg e2 plus 2.5 mg DHG Abbreviations: MPA, medroxyprogesterone acetate; NeTA, norethindrone acetate; DRSP, drospirenone; DHG, dydrogesterone; Cee, conjugated equine
estrogen; e2, 17β-estradiol.
estrogen-progestogen, excess of estrogen, pro- performed on HT users with bleeding. As no practice longed use of estrogen without association of ade- guidelines to help clinicians in managing their patients quate doses of progestogen in women with a uterus, have been available till now, this review offers some abnormal influence of specific local factors, pres- rationale recommendations. It is important to highlight ence of arteriovenous abnormalities in the uterus, that any action to stop the bleeding at an appropriate and myoendometrial alterations not identified in the time should be based on the correct identification of initial assessment of the patient.9,62–64 Despite the the underlying cause.34 Specific objectives for man- strong recommendation not to start HT in the pres- aging abnormal bleeding during HT are provided in ence of uterine abnormalities to ensure better com- Table 5. All the recommendations proposed in this pliance with treatment, uterine pathologies such as review are based on the current knowledge of the fibroids, polyps, and adenomyosis still seem to be role of sex steroids in menstrual physiology; inter- responsible for 27% to 30% of reported cases of actions between sex steroids and endometrium; and abnormal bleeding associated with HT.11,65,66 the role of growth factors, interleukins, and MMPs in abnormal endometrial bleeding. Previous publica- Management of abnormal bleeding tions concerning HT and bleeding management have during hormone therapy been extensively reviewed.7,11,35,46,67 There is little consensus regarding what to do about As an initial and general preventive measure, it persisting bleeding or when reinvestigation should be is important to tailor the regimen to the needs of Clinical Medicine Insights: Women's Health 2013:6 HT bleeding management Table 5. Proposed actions for the management of abnormal
an option for starting HT is to add a progestogen to bleeding with hormone therapy in climacteric women.
reverse the effects of unopposed estrogen in a cyclical way. At least 10 days of the progestogen agent is • Reassess the patient's understanding.
• Check absorption/distribution of the hormones required to assure a secretory transformation and prevent endometrial hyperplasia. The most com- • Consider the regimen in use.
monly used progestogens are medroxyprogesterone • Assess the time/characteristics of the bleeding.
acetate and noresthisterone acetate.7 If the use of a • Exclude intercurrent or unidentified organic causes in cyclical progestogen is the chosen regimen, it is nec- the first assessment.
essary to monitor eventual ovulation to synchronize the moment of starting the exogenous administration individual women and identify those with a higher of the progestogen with ovulation.70 In the continua- risk of bleeding (Table 6). Though it seems to tion of this regimen, the progestogen should be main- have no correlation between endometrium thick- tained cyclically for 12 to 14 days each month.71 If ness, endometrial histology findings, and bleeding prolonged and/or profuse bleeding occurs when the patterns, biopsy is recommended when abnormal progestogen sequence is stopped, the cause may be bleeding persists beyond the first 6 to 12 months an either too low or too high progestogen dose or of use or when it occurs after a long period of because the endogenous estrogen production is now amenorrhea.6,7,9,68,69 The appropriate choice of the insufficient for assuring an adequate proliferation of estroprogestogen combination seems to be relevant the endometrium.
for minimizing the bleeding. However, regarding In the case of a too-low progestogen dose, the the control of abnormal bleeding, there is no robust bleeding may start before the end of the progestogen data indicating any advantage of one estrogen or sequence, imitating what takes place in the luteal phase progestogen over another.8,11,26 As a rule of thumb, with insufficient progesterone production.70 In this two basic actions are recommended for the treat- case, the progestogen should be increased sooner, usu- ment of abnormal bleeding during HT: (1) ensure ally by 2.5 mg of adenosine monophosphate (AMP) that there is no underlying organic disease and or an equivalent amount of another progestogen in the (2) stop the undesired bleeding.
first 36 hours of bleeding; after two days of bleeding, the addition of the progestogen does not have the same Management of abnormal bleeding effectiveness in stopping the abnormal bleeding.6,72 In in users of cyclical progesterone/ the continuation of this regimen, the new progestogen dose should be maintained. On the other hand, if the In the premenopausal patient suffering hot flushes progestogen dose is too high, the bleeding may be but still with some endogenous production of estro- characterized by prolonged spotting for a few days. As gen and deficient or absent secretion of progesterone, a consequence of the estrogen receptor depletion,47,73 the progestogen dose should be decrease thereafter. The adjustment of the progestogen dose based only on Table 6. Profile of users with higher risk of abnormal
bleeding during oral hormone therapy.
time of appearance and the physical aspect of bleed- ing is still speculative, and more controlled studies are needed. If patients present abnormal bleeding after • Low level of education a period of time receiving this regimen, the ovarian • Perimenopause estrogen production could be reassessed by measuring Little motivation • Users of co-medications both estradiol and follicle-stimulating hormone (FSH) – Anticoagulants levels at an interval of at least seven days after stop- ping the hormone.74 If the estradiol levels are normal – Anticonvulsants • Users with chronic gastrointestinal diseases and the FSH levels are still low, the cyclical addition – Celiac disease of progestogen could be maintained. If the FSH level – Ulcerative colitis is high, the regimen should be changed to a combined – Crohn's disease Clinical Medicine Insights: Women's Health 2013:6 de Medeiros et al Management of abnormal bleeding during inhibitory impact on the endometrium.13,40,46 There combined sequential hormone therapy have been no robust clinical trials that have addressed Sequential HT is also recommended in the premeno- these issues yet, and sometimes interventions may be pause and perimenopause periods, while some ovarian activity still is present.71 The most common prepa- In around 36% to 50% of users of this regimen, rations used in this regimen are shown in Table 3. unexpected bleeding occurs in the progestogen phase Differences between menstruation and progestogen before the end of the progestogen tablets.15,50,76 For withdrawal bleeding are probably due to endometrial practical purposes, this bleeding can indicate insuf- exposure to different estrogen or progestogen types, ficient estrogen/progestogen absorption, failure to relatively low estrogen endometrial exposure in HT, have taken the doses correctly, insufficient estrogen and continuation of estrogen administration without dose, or more likely, insufficient progestogen dose, decreasing it through the bleeding phase. After the pro- particularly if the endometrial biopsy reveals the gestin sequence withdrawal, the continual ingestion presence of mitoses.29,68 Usually the users of this regi- of exogenous estrogen at the correct dose guarantees men with full secretory transformation of the endo- re- epithelization of the endometrium and cessation of metrium present normal cycle length and scheduled the bleeding within a few days.7,26,70,75 bleeding after stopping the tablets containing the pro- When prescribing this regimen to women with gestogen.15 Those with shorter cycle length, in whom ovulatory but irregular cycles, it is also necessary to the bleeding starts while the women is still taking synchronize the endogenous production of ovarian the progestogen tablets, may present endometrium steroids with the exogenous estroprogestogen admin- with different histological aspects.15,68,76 The current istration in the first month of treatment.70 A practical recommendations to correct the bleeding consist of method to get this condition is to wait for the next increasing the progestogen dose and reviewing the spontaneous mentrual flow before starting the HT. patient three months later.60,70,77 If the bleeding was When abnormal bleeding occurs during this regimen not resolved, another progestogen with greater endo- the following crucial points should be considered to metrium atrophic effect should be introduced.26,46,57,78 assure a correct management: (1) whether the ocur- In case of spotting before the 10th day of the proges- rence of bleeding is in the estrogen or progesterone togen sequence, the progestogen/estrogen ratio may phase, (2) the duration and volume of the bleeding, be to high, and increasing the estrogen dose seems (3) whether there is a prolonged period of amenor- to be the most appropriate measure.8 If this measure rhea after starting the HT and before the occurrence is unsuccessful, a reassessment of the endometrium of the abnormal bleeding, and (4) the possibility of should be scheduled. Bleeding occurring after the interference of concomitant medication.7,75 10th tablet containing progestogen suggests both Unpredictable bleeding in the initial estrogen an excess of estrogen or low progestogen dose.9,37,77 phase may be a consequence of an insufficient estro- Increasing the progestogen dose is recommended as gen dose, error in taking the hormone, deficient an initial measure.46,79 Failing this measure, the dose absorption, accumulation of estrogen, or even an should be balanced by lowering the estrogen.31,39 If unbalanced or unsuitable type of progestogen being none of these measures are successful, a change of HT administered.14,16 The bleeding in the initial estrogen regimen should be considered.6 Even though data are phase has the characteristic of prolonging the bleed- still limited, switching the sequential composition to ing initiated after stopping the progestogen sequence. a combined continuous regimen at around two years Clinical recommendations in this case consist of veri- after the mean age of menopause is recommended, fying any alteration in absorption to assure greater with the purpose of reducing irregular bleeding.8,80 rigor in the regularity of taking doses, adjust the estro- gen or progestogen dose, and reassess the condition Management of abnormal bleeding in of the endometrium.7,9 A commonly recommended combined continuous hormone therapy procedure is to increase the estrogen dose or reduce Adequate management of abnormal bleeding in users the progestogen, or, even if the progestogen is nore- of this regimen must consider that the abnormal bleed- thisterone, change it to a progestogen with a lower ing may occur due to greater endometrial sensitivity Clinical Medicine Insights: Women's Health 2013:6 HT bleeding management to the estrogen or progestogen, endometrial atrophy, could be considered as an adjuvant measure in the endometrial decidualization, insufficient formation management of women with excessive bleeding dur- of estrogenic receptors, vascular abnormalities, or ing HT.89,90 The administration of doxycycline as an fibrous endometrial atrophy.20,21 The occurrence of MMP inhibitor may inhibit proteolysis and degrada- bleeding depends on the type, dose, and balance of tion of the extracellular matrix and reduce inflamma- the proportions of estrogen and progestogen.57,81 The tory cytokines in endometrium,89 but its clinical use most common preparations used are shown in Table 4. is still controversial in treating abnormal bleeding in The main form of presentation of bleeding in this reg- women using oral hormonal contraceptions.91,92 Its use imen is the appearance of unscheduled spotting rather to decrease bleeding in HT needs to be determined in than bleeding.82 Unfortunately, the pattern of bleed- future studies. As antioxidants (vitamin E) and fla- ing seems to show no distinction between types and vonoides (vitamin B complex) have been shown to be doses of the sex steroids used.32 In clinical settings, effective in correcting vascular fragility and stabilizing due to different bioavailability and potency, the type the vessels, the therapeutic effect of these preparations of progestogen should be taken into consideration.83 as adjuvant measures in HT abnormal bleeding could As with continued use of HT, the cumulative rate be tested.93,94 Vitamin E has been useful in reducing of amenorrhea is increased; in the first six months, the abnormal bleeding in users of low-dose progestogen woman should only be followed, giving her confidence alone but not in HT users.94 In case of an excessive while waiting for the complete cessation of bleeding progestogen effect with reduced estrogen receptor over time of usage.16,31,32 As a general recommenda- density and increased vascular fragility, the intermit- tion, when bleeding persists for more than 12 months, tent use of low-dose antiprogestogen to correct abnor- a reassessment of the endometrium should be carried mal bleeding in HT may also be investigated.95,96 out. If the endometrium is normal at his point, the estrogen dose should be decreased,57,84,85 but if the endometrium is underdeveloped, the estrogen dose Even though the recommendations presented in this should initially be increased.7 There is no proof that review are essentially based on the pathophysiologi- these interventions are particularly effective, how- cal effects of sex steroids on the endometrium, grow- ever.8,35 If these procedures are not successful, chang- ing knowledge of the newer intimate paracrine and ing the progestogen to norethisterone acetate, which intracrine mechanisms involved in endometrial bleed- has a more intense atrophic effect, could be tried.19 ing have supported testing new agents for the man- Attempts to increase the progestogen dose are gener- agement of uterine abnormal bleeding.89–91 Literature ally ineffective,86 but this can also be tested.40,55,60,80 In supporting the effectiveness of the different interven- the last decade, a reduction of 50% in the occurrence tions for controlling abnormal bleeding during HT is of abnormal bleeding has been observed by reducing still limited. More controlled studies are needed to the estrogen dose or even by decreasing doses of both examine the importance of the physical aspects and timing of bleeding in determining the best clinical procedure. In the same way, research to adequate a Adjuvant measures and future directions particular combination of estrogen, progestogen for an individual woman's characteristics is still needed. The ultimate cause of abnormal endometrial bleed- As general guidance, it is important to ensure that ing during HT treatment is capilar disfunction, so this both the myometrium and endometrium are normal review points out that an adequate approach should before starting any HT regimen. Once structural pel- aim to (1) increase vascular stability, (2) reduce pro- vic conditions have been ascertained, any subsequent teolysis of the vascular wall and extracellular matrix, bleeding may be controlled or corrected by appropri- and (3) maintain epithelial integrity and normal ate adjustment of doses and types of sex steroids or even by changing the regimen. If these measures are Taking into account a possible excess in vasodi- unsuccessful, the use of new agents such as metallo- latating prostaglandin production with any HT regi- proteinase inhibitors, VEGF inhibitor, or progesterone men, the use of nonsteroidal anti-inflammatory drugs antagonists could be considered as adjuvant therapy.
Clinical Medicine Insights: Women's Health 2013:6 de Medeiros et al 4. Tonkelaar ID, Oddens BJ. Determinants of long-term hormone replacement The authors thank Biomed Proofreading for English therapy and reasons for early discontinuation. Obstet Gynecol. 2000;95: copyediting of the manuscript.
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reviewed and approved of the final manuscript.
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Author(s) disclose no potential conflicts of interest.
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provided to the publisher signed confirmation of com- 18. PEPI Trial. Effects of estrogen or estrogen/progestin regimens on heart pliance with legal and ethical obligations including but disease risk factors in postmenopausal women. The postmenopausal not limited to the following: authorship and contribu- Estrogen/Progestin Interventions (PEPI) Trial. The writing group for the PEPI Trial. JAMA. 1995;273:199–208.
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that they have permission from rights holders to repro- 22. Hickey M, Doherty DA, Fraser IS, Sloboda DM, Salamonsen LA. Why does duce any copyrighted material. Any disclosures are menopausal hormone therapy lead to irregular uterine bleeding? Changes to made in this section. The external blind peer reviewers endometrial blood vessels. Hum Reprod. 2008;23:912–8.
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