Clinical profile of women with VVA who are not candidates for local
vaginal oestrogen therapy
Authors
Rossella E. Nappi1*, Filippo Murina2, Giuseppina Perrone3,Paola Villa4, Nicoletta Biglia5.
Affiliations
1. Research Center for Reproductive Medicine, Gynecological Endocrinology and Menopause, IRCCS S. Matteo Foundation, Dept of Clinical, Surgical, Diagnostic and Paediatric Sciences, University of Pavia, Pavia, Italy; 2. Lower Genital Tract Disease Unit, V. Buzzi Hospital-University of Milan, Milan, Italy; 3. Università di Roma "Sapienza", Dipartimento di Scienze Ginecologiche, Ostetriche e Scienze Urologiche. Policlinico Umberto I - Roma, Italy; 4. Department of Obstetrics and Gynaecology, Catholic University of Sacred Heart, Rome, Italy; 5. Department of Obstetrics and Gynaecology, The University of Torino School of Medicine, Torino, Italy.
Corresponding author:
Prof. Rossella E. Nappi, MD, PhD
Research Centre for Reproductive Medicine Section of Obstetrics and Gynecology IRCCS Policlinico San Matteo Piazzale Golgi 2 27100 Pavia, Italy Phone: + 39 0382 501561 Fax: +39 0382 536176 Email: renappi@tin.it Word extension: 3450
Abstract
Vulvar and vaginal atrophy (VVA) is a chronic medical condition in postmenopausal women, which is predominantly due to a permanent cessation of ovarian oestrogen production. Current available treatment options for VVA are over-the-counter (OTC) symptomatic relief products or local oestrogen therapy (LET) aiming to treat this underlying atrophic condition. Recent surveys indicated that these products decrease sexual spontaneity, are messy and indiscrete. Ospemifene is an oral daily drug, which has proven to treat vaginal dryness and dyspareunia effectively. However, despite the comparable efficacy of ospemifene versus placebo to oestrogen versus placebo, ospemifene is currently indicated for women, who are not candidates for LET. It is up to the gynaecologist to make an appropriate therapeutic decision. However, there are potential candidates who have not been considered for ospemifene and yet would benefit from this treatment, such as breast cancer survivors, or patients unable to perform or that have problems performing vaginal insertion/application of oestrogen based treatments, such as women that suffer from prolapse. Likewise, a patient’s concern for hormone treatment safety, treatment regimens complexity or cross contamination with their partner are potential issues to consider when prescribing treatment for VVA in order to provide the best therapeutic option for patients who are generally not compliant with their current therapy.
Keywords
Vulvar and Vaginal Atrophy; Genitourinary syndrome of menopause, Postmenopausal Women; Sexual Relationships; Vaginal Dryness; Dyspareunia; Ospemifene; SERM
Introduction
Vulvar and vaginal atrophy (VVA) is a chronic medical condition in women suffering from hypoestrogenism, such as postmenopausal women.1,2 Other causes of low oestrogenization
in pre-menopausal women, such as lactation, breast cancer treatment with a gonadotropin-releasing hormone (GnRH) analogues and use of certain medications, are situations that usually are resolved spontaneously when oestrogen levels are restored. However, during the postmenopausal phase the permanent lack of oestrogenization of the vulvovaginal tissue causes vaginal epithelium thinning, resulting in reduction in lactobacilli that normally produce lactic acid, leading to an increase in vaginal pH and overgrowth of other bacteria which can cause symptomatic vaginal infections and inflammations.3,4 The women may also experience
symptoms like vaginal dryness, soreness and irritation, as well as dyspareunia.1,3–6 Up to 50% of
all postmenopausal women suffer from VVA symptoms; but despite this high prevalence and the associated burden, VVA is still heavily underdiagnosed and undertreated.5,7
Current available treatments: over-the-counter (OTC), local oestrogen therapy (LET) and systemic hormone therapy (HT)
Currently available treatments can be divided into over the counter (OTC) non-hormonal vaginal moisturizers, lubricants designed to treat VVA symptoms, prescription of local oestrogen therapy (LET) and systemic hormonal therapies (SHT). Over the counter non-hormonal vaginal moisturizers and lubricants treatments uniquely treat symptoms and not the underlying condition of VVA. These treatments address vaginal dryness and reduce itching, burning and dyspareunia, however, they have no effect on the loss of elasticity and compliance of vaginal walls8. Local oestrogen therapy and SHT, on the other hand, attempt to treat the
underlying condition and may be used when VVA symptoms are part of the climacteric syndrome.
Recently, postmenopausal women's experience with and perception of VVA symptoms was characterised by the REVIVE (REal Women’s VIews of Treatment Options for
Menopausal Vaginal ChangEs) survey, conducted separately in the USA9 and in Europe10. The
results indicated that 7% (n=222) and 9% (n=341) of VVA sufferers in the USA and Europe (respectively) are currently being exclusively treated with prescription therapy, while 29% (n=878) and 30% (n=1138) respectively, preferred OTC treatment only (Table I).9–11
The REVIVE survey also showed that a large percentage of postmenopausal women were currently treated with OTC treatment (30%), only 9% were current users of prescribed VVA therapies and 10% were former users of prescribed VVA therapies.9,10 A 2006 meta-analysis of
19 randomized clinical trials involving 4162 postmenopausal women assessing the efficacy of available oestrogenic preparations showed that oestrogenic preparations are more effectively than non-hormonal gels and/or placebo-products or placebo-substances.12 This analysis showed
that oestrogenic preparations local or systemic (creams, rings or tablets) relieve symptoms and appeared to be effective treatments for VVA (Table II).12
However, many women are reluctant to use SHT and LETs.9,11,13 The results of a
number of studies, including the WHI in the USA and the one-million-women study in the UK showed an increased breast cancer risk with oestrogen and progestin combination, which has led to the perception of oestrogen as a harmful treatment.14–17 This perception still persists despite
later publications showing that the risk has been overestimated and limited to selected types of oestrogens and progestins combinations, whereas oestrogens alone seem to be protective instead.18–20 The European and USA REVIVE surveys revealed that menopausal women
currently using prescription therapy had concerns on long term safety (Europe and USA: 21% and 41%, respectively), hormonal exposure (17% and 35%), breast cancer risk (11% and 30%), and side effects in general (16% and 26%) (Table I).9–11 The EMPOWER study has confirmed
these fears showing that women in the USA with VVA symptoms were mostly concerned over the treatments side effects (43%) and the safety of hormone treatment.13
In breast cancer survivors the safety issue of local oestrogens is still under debate as few studies have been conducted to address this question.21 In a study of 1472 breast cancer patients,
cancer, this small number of patients studied precluded a definitive result.22 In a small pilot
study in18 symptomatic breast cancer patients, oestriol cream or tablets were found to be effective for relieving urogenital atrophy, were well tolerated and associated with a minimal increase of serum oestrogen levels during treatment .23 However the contrary can be said for a
study of 48 postmenopausal women: 24 control participants receiving only AI and 14 and 10 patients using VE tablets and ring respectively.24 This study concluded that intravaginal
oestrogen preparations, although attractive for the treatment of VVA, should be used with caution in hormone receptor positive breast cancer survivors.24
The HABITS trial showed an increased risk of breast cancer recurrence in the group treated with SHT, with an HR of 3.3 (95% CI: 1.5-7.4) as compared to control group.25
Conversely, the Stockholm study showed no significantly increased recurrence risk among 378 postmenopausal breast cancer patients (HR: 0.82; 95% CI: 0.35-1.19) receiving SHT.26 A joint
analysis of the trials was performed showing an increased risk of recurrence amongst treated patients (HR 1.8: 95%CI 1.03-3.1) and both trials were prematurely stopped.25,26An excess of
breast-cancer recurrences was also observed in the LIBERATE study, where breast cancer patients with climacteric complaints were treated with tibolone, a synthetic oestrogen used for treatment of symptoms of menopause and prevention of osteoporosis.27 In this study 15.2%
(n=1556) of the women treated with tibolone vs 10.7% of the women in the placebo group had breast cancer recurrence (HR 1·40 [95% CI 1·14–1·70]; p=0.001).27 A small prospective study
measured serum oestradiol, follicle stimulating hormone (FSH) and luteinising hormone (LH) levels in seven postmenopausal women using vaginal oestrogen preparations whilst on AIs for breast cancer and showed a significant increase in the serum oestradiol levels28 which might
potentially lead to increased risk of recurrence. The North American Menopause Society 2013 Position Statement concluded that the use of oestrogen local therapy for VVA in breast cancer survivors should be reserved for those who are unresponsive to non-hormonal remedies, it should be preceded by an informed consent process and recommend caution for patients receiving AIs.29 The use of local oestrogen therapies remains contraindicated in both Europe and
The REVIVE surveys also indicated that menopausal women using prescription vaginal local treatments were dissatisfied with the application procedures which were described as “messy” (20% and 13%), “not discrete” (3%) and “not an oral pill” (7% and 11%) (Table I).10,11,30 In addition, women treating VVA with LET indicated in the REVIVE survey additional
issues to those previously mentioned, such as disruption and interference with sexual spontaneity (USA and Europe: 8% and 9%) and the excess vaginal discharge (15% and 13%) (Table I).9–11,35,36 The REVIVE survey results from both Europe and the USA indicated that
women may be not willing to adhere to either to SHT or LET due to concerns or dissatisfaction with available treatments (Table I).9–11 The general dissatisfaction with current treatment has led
to the development of an oral VVA treatment, ospemifene (Senshio®), a selective oestrogen receptor modulator (SERM).
Selective ER modulators as new treatments
Oestrogen receptor (ER) targeting SERMs, similarly to oestrogen, exert their physiological effects by targeting ER.37,38 The ER has a wide-ranging profile of transcriptional
activation and is dependent on the ER subtype (α and β), tissue type, and co-regulator protein presence.37,38 The binding of a SERM to the ER results in specific conformational changes of the
ER-SERM combination which, depending on the SERM, would in turn activate or repress the oestrogen pathway.37,38 The juxtaposed effects mean that SERMs can function as an oestrogen
antagonist in certain tissues (anti-oestrogenic effect) and as an oestrogen agonist in others (oestrogenic effect).38 Therefore, the physiological effects induced by SERM binding to ER are
SERM and tissue specific and can differ to those effects induced by oestrogen.37,38
This characteristic has made them excellent clinical tools leading to their approval for use in various clinical applications such as treatment and prevention of breast cancer and osteoporosis.37,38 One of the first approved SERMs was tamoxifen, currently used as adjuvant
therapy in primary breast cancer, as treatment in metastatic cancer and also approved for prevention of breast cancer in high-risk women.39–42 Other SERMs are currently being used
(raloxifene and bazedoxifene) or are under development (lasofoxifene) for treatment and/or prevention of osteoporosis in post-menopausal women.41,43 Further uses of SERMs also include
female infertility, whereby SERMs such as clomiphene citrate marked the beginning of a modern era of assisted reproductive technology.44,45
Pharmacologic profile of the SERM ospemifene
The SERM ospemifene (Senshio®) recently became available in Europe for the treatment of
moderate to severe symptomatic vulvar and vaginal atrophy (VVA) in post-menopausal women who are not candidates for local vaginal oestrogen therapy. The effect of ospemifene is tissue specific and shows an oestrogenic impact in bone and vaginal tissues, weak partial agonist/antagonist effects in the uterus and antagonistic and anti-proliferating in breast tissues.46– 48
Oestrogenic and agonistic effect of ospemifene: bone, uterine and vaginal tissues
Even though ospemifene shows a weak antagonist effect in the endometrium with a weak intrinsic agonistic property, only minimal effect has been observed in clinical trials in the endometrium tissue.47,49,50 No clinically significant changes have been observed in the
endometrial thickness, furthermore, no cell proliferation was observed in the clinical studies, as evaluated by Ki-67 markers for endometrial proliferation and histological assessment of endometrial biopsies at one year.47,50–52 Ospemifene was, proven to be safe for the endometrium
in the Phase II/III clinical trial program in postmenopausal women with up to 52 weeks of daily oral exposure of 60mg versus placebo.52 There was no increased incidence of endometrium
cancer or hyperplasia compared to placebo.52 The effects of ospemifene on bone turnover in
women who were postmenopausal but not on treatment for osteoporosis was examined in two Phase II trials.47,53,54 Compared with placebo, these Phase II clinical trials showed that
ospemifene may have bone-protective effects in postmenopausal women.55 Ospemifene has
been shown to have a clear oestrogenic effect on vaginal epithelium.
Antagonistic and anti-proliferating effect of ospemifene: breast tissue
The analysis of ospemifene effect in human breast tissue of postmenopausal women using ex vivo explant cultures showed an inhibitory effect on mammary tissue similar to that of raloxifene and tamoxifen.56 The investigation of ospemifene in regards to its effect in breast
tissue in a clinical setting is still preliminary as, although no increase in breast tumours have been observed in the clinical trials performed, the follow-up periods of these trials have been too short in order to fully evaluate ospemifene’s effect on breast tissue.57–59 Nevertheless, three
of the clinical studies which were conducted to evaluate the overall long term safety of ospemifene included mammograms to assess breast safety.60–63 A 52-weeks Phase III study in
women with signs of VVA assessed breast safety via palpation and mammography at screening and after 52 weeks of daily-administered ospemifene (60mg/day). No clinically significant changes were observed at any point throughout the study from baseline to week 52.55 Although
there were only few patients that had a history of breast cancer in these clinical trials, no breast cancer recurrence was observed with ospemifene use to date.57,60–62
VVA patient treatment with SERMs: Ospemifene efficacy and safety
Three double-blind, placebo controlled clinical studies were submitted in support of the efficacy of ospemifene for VVA treatment: two 12 week Phase III studies (study 15-50310 and 15-50821) for efficacy and a 52 week Phase III study (study 15-50718) for long term safety, where long term efficacy data were additionally collected. These studies showed statistically significant results for the three objective efficacy variables (percentage of parabasal cells, percentage of superficial cells and vaginal pH) compared to placebo, an effect that was maintained after 52 weeks.58–61,64–66 Ospemifene 60 mg showed to be superior to placebo on
oestrogens showed that the efficacy of ospemifene 60 mg/day versus placebo was comparable to, or better than, that seen in local oestrogens versus placebo.60
The most common treatment-related AEs of ospemifene in clinical trials were hot flushes (7.5% vs. 2.6% for ospemifene with respect to placebo); vaginal discharge (3.7% vs. 0.3%) and headache (3.1% vs. 2.4%).68 Hot flushes was the most common AE responsible for treatment
discontinuation, however, only 0.9% of the patients discontinued treatment due to this AE. The majority of hot flushes waned after 4 weeks of ospemifene treatment and ospemifene did not worsen already existing hot flushes in women experiencing moderate to very severe hot flushes.69 Other AEs that led to discontinuation were headache (0.6%) nausea (0.4%), muscle
spasms (0.4%) and vaginal discharge (0.4%).68 Additionally, caution is suggested for subjects
with active or past history of venous thromboembolic events (VTEs), including deep vein thrombosis, pulmonary embolism and retinal vein thrombosis and ospemifene should be issued on a case by case basis. While clinical studies showed no increase in venous thromboembolism (VTE) the exact incidence risk of VTE in ospemifene treated women, the reliably could not be estimated due to wide confidence limits.68
In all the trials together, only two cases of breast cancer were reported in the placebo group but none in ospemifene arm (60 mg/day).1,57,58,61,64–66 The safety of using ospemifene
concomitantly with oestrogens or other SERMs, such as tamoxifen, has not been studied and its concurrent use is not recommended. Ospemifene is, therefore, not recommended for patients with suspected breast cancer or patients undergoing active treatment for breast cancer. Ospemifene should be used for the treatment of VVA only after the treatment of breast cancer, including adjuvant therapy, has been completed. Vaginal atrophy in breast cancer survivors is highly prevalent and ranges from 23% to 61%.4,28,70 Furthermore, the use of aromatase inhibitors
(AIs) as adjuvant therapy in hormone-sensitive tumours increases the severity of VVA as they decrease the levels of circulating oestrogen and these effects are even greater in third-generation AIs.4,28,70
In Europe, ospemifene is currently indicated for the “Treatment of moderate to severe symptomatic VVA in post-menopausal women who are not candidates for LET”. Although
women with contra-indications to LET are clearly ‘not candidates for LET’, it is ultimately at the discretion of the treating physician whether to prescribe ospemifene in that case or not. In addition, there are a number of other conditions which are not necessarily contra-indications, but still would make patients ‘not candidates for LET’.
Not candidates for local vaginal oestrogens
As previously described, postmenopausal women who have contraindications to local oestrogens are not candidates for LET. Some of these contraindications are similar for both LET and ospemifene. It is therefore of vital importance to understand which of these patients that are contraindicated for (local) oestrogen, could be possible candidates for ospemifene (Figure 1). Patients who have survived breast cancer and have completed their (adjuvant treatment) are not candidates for local oestrogen due their history of breast cancer,71,72 but can use ospemifene.68
The elevated prevalence of vaginal atrophy in breast cancer survivors and the exacerbated VVA symptoms caused by chemotherapy and by aromatase inhibitors (AI) adds to their already existing problems.4,21
Ospemifene is the only prescription drug available for women with VVA and a history of breast cancer after the treatment of breast cancer, including adjuvant therapy, has been completed (Figure 1).61,73 Additionally, a history of a hormone dependent tumour is commonly
a contraindication for any oestrogens use, including local oestrogens.74 Although ospemifene is
contra-indicated in the case of suspected or active sex-hormone dependent malignancy (e.g. endometrial cancer) it can be used after the successful treatment of such cancers.68
Whilst most labels of oestrogen containing preparations include a contra-indication in case of acute liver disease or a history of liver disease as long as liver function tests have failed to return to normal, no dose adjustment is necessary for ospemifene in patients with mild or moderate hepatic impairment (the pharmacokinetics of ospemifene has not been evaluated in patients with severe hepatic impairment (Child-Pugh Class score >9)).68 Similarly, oestrogens
SERMs, including ospemifene, have not shown such an effect, so ospemifene can be used in women with porphyria. Finally, hypersensitivity to active substances and/or excipients of the local treatment have clear contra-indications to their use but not to an oral tablet like ospemifene.68
Another potential category of women who are not candidates for LETs use are women who do not want to use SHT or LET for different reasons, ranging from fear of cancer, inconvenient way of administration, interference with the spontaneity of sex, fear for cross contamination of the partner or inefficacy.9–11. Most women in the REVIVE surveys commented
on the messiness of the administration (20% and 13% in USA and Europe), the lack of discretion (3% and 3%) and the interference with sexual spontaneity (9% and 8%), conditions that may impact compliance and need to be considered when prescribing a local vaginal oestrogen (Table I).9–11 This dissatisfaction may affect adherence to treatment.9–11,59
Non-adherence to therapy is exceedingly costly and brings no relief to the patient.76 Furthermore,
patients often do not inform the health care provider about their dissatisfaction with the treatment and, more often than not, live with the symptoms or find less controlled treatment alternatives. Patients that fall in this category include those that have concerns about: the safety of hormone treatments (41% and 21% in USA and Europe REVIVE surveys, respectively), difficult dosing schedule (13% and 4.5%), potential cross-contamination in partner (11% and 3.4%) and safety in long term use (41% and 21%) (Table I).9–11
Women who are not willing to use LETs for the aforementioned reasons are not candidates for local vaginal oestrogens, can be considered for ospemifene.Furthermore as with any treatment, not all patients will find the desired effects with the prescribed therapy (23% and 13%), and patients often need to try various treatments to find relief, including ospemifene (Table I).9–11
Other groups of women who are not candidates for local vaginal oestrogens are those who are physically unable to administer local treatments. These might include obese women. In postmenopausal women, BMI ≥30 kg/m2 has been independently associated with an increased
which have shown an inverse correlation with BMI.77Therefore, sexually active postmenopausal
women, which may find applying local therapies difficult due to their size may not be candidates for local oestrogens therapy, but since ospemifene is an oral tablet may find this more convenient.68 Since body weight was not a significant covariate on the pharmacokinetics
of ospemifene, no dose recommendations for obese and underweighted patients were considered required.68
Patients that remain handicapped due to a stroke, particularly in the case of hemi-paresis or patients that suffer from tremors commonly associated with Parkinson’s disease (PD) can also find local administration difficult. In this population, ospemifene should be issued on a case by case basis.
Women with VVA and uterine prolapse are another subset of patients that are not candidates for local vaginal oestrogen use. Women that suffer from prolapse have problems not only with creams/gels but also with alternative administration routes such as local oestrogen tablets/rings/vaginal suppositories which may not stay in situ, making them not candidates for local oestrogen therapy and they may find an oral tablet like ospemifene more convenient.68
Conclusions
Currently available local treatments for VVA (topical oestrogens or moisturizers and lubricants) are often used as first-line treatment. However, not all women are candidates for local oestrogen therapy. Patients with a history of breast cancer or other hormone dependent cancer have a contra-indication to (local) oestrogen use as do patients with acute liver disease or a history of liver disease where the liver function tests have failed to return to normal, patients with porphyria and with hypersensitivity to active substances and/or excipients of the local treatment. Ospemifene is an oral daily drug for post-menopausal women with moderate to severe symptomatic vulvar and vaginal atrophy (VVA) who are not candidates for local vaginal oestrogen therapy, which has been proven to have comparable or better efficacy/safety compared to local vaginal oestrogen60and should be considered for these populations. Other
patient populations which may not be candidates for local oestrogen therapy include those who are physically impaired to apply local treatment (e.g. obesity, Parkinson, after stroke, etc.) and those not willing to accept or to continue vaginal treatment due to concerns about messiness, inconvenience, cross contamination of the partner, interference with sexual spontaneity, complex treatment regimens, fear of hormones and unwillingness to touch the genitals. Adoption of ospemifene as an alternative to current treatments for VVA may provide a greater opportunity for a therapeutic response of VVA sufferers.
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Conflict of Interest Statement
Rossella E. Nappi has a financial relationship (lecturer, member of advisory boards and/or consultant) with Bayer HealthCare AG, Endoceutics, Boehringer Ingelheim, Ely Lilly, Gedeon Richter, HRA Pharma, Merck Sharpe & Dohme, Novo Nordisk, Pfizer Inc, Shionogi Limited, TEVA Women’s Health Inc. Nicoletta Biglia has a financial relationship (lecturer, member of advisory boards and/or consultant) with Gedeon Richter, Shionogi Limited, Merck Sharpe & Dohme, Italfarmaco SpA. The other authors have no conflicts of interest.
Acknowledgements
Manuscript writing and editorial support was provided by Emili González-Pérez, PhD and Nerea Gallastegui, PhD from TFS Develop with financial support provided by Shionogi. The study was sponsored by Shionogi.
FIGURE LEGENDS
Figure 1.
VVA prescription treatment; advantages/disadvantages, contraindications and patient candidates of both oestrogen and ospemifeneTABLES
Table I.Views of participants using prescription therapies for VVA of the REVIVE USA and EU studies on current therapies9–11
Table II. Prescribed products for VVA: Treatment and dosage. Adapted fromOspemifene (OSPHENA) National Drug Monograph78
Table I. Views of participants using prescription therapies for VVA of the REVIVE USA and EU studies on current therapies9–11
REVIVE USA Prescription vaginal % (n=308) REVIVE EU Prescription vaginal % (n=357)
Issues related to route of administration
Messy 20% (72) 13% (51)
Not discrete 3% (11) 3% (12)
Not an oral pill 11% (40) 7% (28)
Do not like touching body 1% (2) 2% (8)
Issues related to convenience
Interrupts my daily activities/life 3% (10) 2% (6)
Inconvenient to administer 19% (68) 15% (58)
Cannot be sexually spontaneous 9% (32) 8% (31)
Difficult dosing schedule 13% (45) 5% (17)
Procedure of administering treatment 22% (77) 12% (44)
Issues related to side-effects/safety
Concern about breast cancer 30% (108) 11% (43)
Concern about hormone exposure 35% (126) 17% (63)
Concern about safety in long-term use 41% (146) 21% (81)
Vaginal discharge 13% (47) 15% (57)
Concern about other side-effects 26% (92) 16% (62)
Experienced side-effects 4% (15) 2% (6)
Partner absorbing oestrogen 11% (38) 4% (15)
Issues related to efficacy
Vagina not restored to natural state 36% (130) 26% (98)
Not enough relief of symptoms 23% (84) 13% (49)
Takes a long time to start working 10% (35) 12% (46)
Other
Expensive 32% (114) 7% (26)
Table II. Prescribed products for VVA: Treatment and dosage. Adapted from
Ospemifene (OSPHENA) National Drug Monograph
78Active ingredient Administration Dose comment
Hormone therapy
Oestradiol
oral 1-2 mg/day cyclically (3-weeks on/1 week off); transdermal weekly or biweekly intramuscular 10-20 mg/4 weeks
Conjugated oestrogen
oral
0.3 – 1.2 mg/day taken cyclically for 21 days
/month or daily.
Use lowest dose based on patient’s response. Esterified oestrogen oral 0.3 to >1.25 mg/day taken cyclically for 21 days
/month or daily.
Use lowest dose based on patient’s response.
17β-oestradiol (Estring)
vaginal
2 mg. Insert one ring every 3 months; releases 7.5 µg/day Can become dislodged. Difficult to remove or insert.
Oestradiol heihydrate (Vagifem)
vaginal
10 µg & 25 µg Insert 1 tablet once daily for 2 weeks, then 1 tablet twice
a week.
Dissolves slowly over several
hours.
Oestradiol acetate (Femring)
vaginal
0.05 or 0.1 mg/day Insert 1 ring every 3
months. Can become dislodged. Difficult to remove or insert. Oestradiol 0.06% (OestroGel)
transdermal 1.25 gm applied daily.
Oestradiol (Estrace)
transdermal
0.1mg/gm vaginal cream 2-4 gm/day for 1-2 weeks,
then 1 gm/day Administered 12h before intercourse to avoid transmission to partner. Selective Oestrogen modulators
Ospemifene (Senshio)
