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Promestriene

Promestriene (INN) (brand names Colpotrofin, Colpotrophine, Delipoderm) is a synthetic estrogen and glucocorticoid used topically in a 1% cream formulation. It is described as a tropic agent and antiseborrheic. It has not been found to be effective in the treatment of androgenic alopecia or other conditions of cutaneous androgenization.


Scheme
Rec.INN

ATC (Anatomical Therapeutic Chemical Classification)
G03CA09

CAS registry number (Chemical Abstracts Service)
0039219-28-8

Chemical Formula
C22-H32-O2

Molecular Weight
328

Therapeutic Category
Estrogen

Chemical Name
Estra-1,3,5(10)-triene, 17-metoxy-3-propoxy-, (17β)-

Foreign Names
Promestrienum (Latin)
Promestrien (German)
Promestriène (French)
Promestrieno (Spanish)
Generic Names
Promestriene (OS: DCIT)
Promestriène (OS: DCF)
Brand Names
Colposeptine (Promestriene and Chlorquinaldol)
Grünenthal, Ecuador; Merck, Peru; Merck, Turkey; Merck Serono, China; Teva, Hong Kong; Theramex, Georgia; Theramex, Lebanon; Theramex, Tunisia; Théramex, France; Théramex, Monaco; Théramex, Malta; Théramex, Romania; Theramex-TEVA, Vietnam
Colpotrofin
Teva, Spain
Colpotrophine
Merck, Peru; Merck, Turkey; Teva, Hong Kong; Teva Santé, France; Theramex, China; Theramex, Georgia; Theramex, Italy; Theramex, Lebanon; Theramex, Portugal; Theramex, Tunisia; Théramex, Monaco; Théramex, Malta; Théramex, Romania; Theramex-TEVA, Vietnam; Vifor, Switzerland
Trophoseptin (Promestriene and Chlorquinaldol)
Laboratoire Théramex, Portugal

Promestriene Side Effects

Promestriene is a topical synthetic version of the hormone estradiol indicated for treating vaginal atrophy, the thinning and shrinking of tissues caused by low estrogen levels in postmenopausal women. The symptoms of vaginal atrophy are vaginal dryness, soreness, pain during intercourse and urinary incontinence. There are few reports of any side effects associated with topical promestriene treatment, since a study in the journal “Steroids” notes that less than 1 percent of topically applied promestriene is absorbed.

Vaginal Bleeding
An article from the University of Minnesota School of Nursing reports that women who use various preparations of topical estrogens may experience vaginal spotting and itching.

Pain
The article from the University of Minnesota School of Nursing also notes that women who use topical estrogens may have minor side effects such as headache, back pain and abdominal pain. In contrast to some other topical estrogens, a study published in an Italian journal reports that promestriene is not absorbed through the vaginal mucosa and does not increase circulating levels of estrogen. Therefore, any systemic side effects from promestriene will likely be negligible.

Yeast Infection
The Italian study reported a case of a yeast infection in a woman treated with topical promestriene; however, it did not conclude that the yeast infection was caused by promestriene.

Promestriene, a specific topic estrogen. Review of 40 years ofvaginal atrophy treatment: is it safe even in cancer patients?

Urogenital symptoms resulting from estrogen deficiencyare common problems that impair quality of life andsexuality. Potentially, one out of three postmenopausalwomen could benefit from a vaginal estrogen therapy, butthe fear of systemic absorption limits its use. Promestrieneused vaginally to relieve vaginal atrophy is a locallyeffective estrogen that has not shown systemic estrogeniceffects. Thus, it could be a first-line option for those whonecessitate a minimal or ideally no vaginal absorption,particularly in symptomatic cancer patients. There are littledata available in the literature, mostly consisting of small,open-label, short duration studies, and few randomized-controlled studies. After a long-term market experience(almost 40 years), in 34 countries, and millions of piecesprescribed, the side effects were very rarely reportedin pharmacovigilance data, whereas the effectiveness torelieve atrophy was good. To further improve promestrienesafety, especially in estrogen-sensitive cancer patients,a very low dose is used from the beginning, startingfrom half or less of the usual dose, and then graduallyincreased till the minimum effective dose, whichcould further reduce its already minimal vaginalabsorption.

Introduction

Urogenital symptoms resulting from estrogen deficiencyare common problems that impair quality of life andsexuality. One of the most frequent clinical problemsreported  by  postmenopausal  women  is  dyspareuniabecause of vaginal atrophy.

Vaginal lubricants and moisturizers are commonly used asfirst-line, over-the-counter, treatments of vaginal drynessand dyspareunia, but they need to be applied every day,have only a short-lasting action, and do not relieve thesymptoms completely.

Vaginal estrogens cure vaginal atrophy and effectivelyreduce the corresponding symptoms such as burning,itching, and dyspareunia. They increase the lubrication ofthe atrophic epithelium, reduce vaginal pH, and increaselocal glycogen. This helps restore a ‘normal’ microflorathat reduces infection and inflammation.

All vaginal estrogens are clinically equally effective for thetreatment  of  vaginal  atrophy  at  proper  doses.Potentially, one out of three postmenopausal womencould benefit from using a vaginal estrogen therapy,but the fear of systemic absorption limits their use.

Promestriene is a 3-propyl and 17b-methyl ether ofestradiol that has an efficient action on vaginal atrophywhile it is minimally absorbed.

Promestriene safety is further substantiated by its long-lasting and wide clinical experience. Promestriene wasfirst launched in France in 1974. After many millions ofboxes of both cream and capsules sold in 34 countriesaround the world, there is only one published casereport of a hematocolpometra in an elderly lady thatwas  believed  to  be  attributable  to  prolonged  andcontinuous treatment with promestriene cream. Cervicalstenosis was caused by atrophy existing before localtreatment was started and the intrauterine bleedingcould even be unrelated to promestriene use.

MethodsTo confirm the low absorption and safety of promestriene,a review of all the literature was performed in Pubmedand Scopus; Micromedex was consulted and all thepertinent articles were manually searched and analyzed.All the papers analyzed were concordant on promestrieneefficacy and safety. They have been summarized chron-ologically in Table 1.

it leads to a low plasma concentration, because of lesspenetration into basal membrane.
Estradiol is the principal intracellular human estrogenand it is more potent than estrone and estriol at thereceptor level; it is the primary estrogen secreted beforemenopause. Estrogens modulate the pituitary secretion ofgonadotropins, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) through a negative feedbacksystem; estrogen replacement reduces elevated levelsof these hormones.

The metabolism of promestriene is hepatic throughCYP3A4 and CYP1A2 enzymes; estradiol is reversiblyconverted into estrone and estriol. Topic estradiol alsoundergoes enterohepatic recirculation by conjugation inthe liver, followed by excretion of sulfate and glucuronideconjugates into the bile, and then hydrolysis in theintestine and estrogen reabsorption. Sulfate conjugatesare the primary form found in postmenopausal women.Estriol and their glucuronide and sulfate conjugates arealso excreted in the urine.The  safety  data  of  topical  estrogens  are  available;promestriene can be used in a proper way. Specialrecommendations  must  be  considered  when  usingpromestriene with other CYP34A-substrate molecules.

Promestriene use in patients with cancerThe use of vaginal estrogens is controversial in gyneco-logical oncology patients as they are more likely to develop severe vaginal atrophic symptoms; thus, theyneed it more frequently, but, at the same time, most ofthem have an estrogen-sensitive neoplasm and fear itspossible systemic effect. The safety data available are soreassuring that promestriene can also be used, in a properway and in selected cases, to treat vaginal atrophy even inpatients with cancer.

The first reassuring and most reliable data on promes-triene  low  absorption  emerged  from  a  randomized,double-blind controlled trial on patients with cancer.Thirty-eight postmenopausal patients, aged 24–60 years,had spontaneous menopause or they were ovariecto-mized at least 1 year before the study. They weretreated for cancer cervix , endometrial, ovar-ian, and breast cancers. All women presented withsexual troubles, mainly genital discomfort (dyspareunia orvaginism). In a double-blind approach, gynecologicalcapsules containing either an estradiol diether (ICD:promestriene) or only the excipient were administeredfor 40 consecutive days. In the treated group, vaginalsymptoms seemed to improve but, at the end of the cure,the FSH, LH, estrone (E1), and estradiol (E2) plasmalevels  were  not found  to be significantly different(P> 0.05) from the pretherapeutic values: estrone (from55.1±7.1 to 58±9.6 pg/ml); estradiol (from 25.5±5.7 to25.7±5.6 pg/ml); FSH (24.8±1.7 to 22.7±1.6 mIU/ml);and LH (27.3±2.1 to 27.1±3.1 mIU/ml). These resultssuggested that promestriene acts on the vaginal mucosa,therefore not being converted back into the hormonefrom which it was derived. Also, in its dietheroxide form,the absorption of promestriene across the Malpighian(vaginal or epidermal) epithelium was very low.The efficacy of promestriene in the treatment of vaginalatrophy was confirmed in a study on 17 patients withcancer treated with a 10 mg soft vaginal suppository.At the physical examinations before and after a 1-monthtreatment, vaginal lubrication and  dyspareunia wereevaluated subjectively using a visual analogue scale.Atrophy was evaluated by a colposcopic examination andalso using Lugol solution, cytology, and vaginal pH.Promestriene relieved significantly all subjective andobjective parameters assessed in these highly sympto-matic patients. Vaginal lubrication improved [3 (2–4) to 5(4–8);P= 0.008] as dyspareunia [6.4 (6–8) to 3 (2–5);P= 0.007] and the mean vaginal pH decreased [5.5(4.8–6.2) to 4.4 (4.2–5.4);P= 0.043]. Colposcopy wasmore reliable and intracervical procedures were feasibleand more tolerated after estrogenization of the cervix,which made low genital tract early diagnosis moreeffective in the nonhysterectomized patients. Vaginalcytology showed four atypical squamous cells of unknownsignificance (ASCUS) before treatment and only oneafter promestriene treatment.

Furthermore,  the  absence  of  a  systemic  effect  ofpromestriene has been confirmed recently even withthe  accurate  and  sensitive  mass  spectrometry.  Thecirculating  estrogenic  pool,  evaluated  by  measuringthe variations in the plasma levels of estrone sulfate(E1S), did not change after 1 month of promestriene treat-ment even in cancer patients with vaginal atrophy.

E1S was measured before and 1 month after vaginalpromestriene treatment (10 mg/day) in 17 patients withsevere  vaginal  dryness  and  dyspareunia  referred  tothe gynecological endocrine–oncological service of theGynecological Oncology Department of the NationalCancer Institute of Aviano, Pordenone, Italy. Patientswere informed of the aim of the study and of the benefitsand risks of promestriene. Two patients were withdrawnduring the study: one started a therapy with letrozole andthe other died, unrelated to the treatment studied.Of the eligible patients, six had cervical cancer, four hadendometrial cancer, three had ovarian cancer, and two had vulvar cancer. Patients’ median age was 48 years(range 26–66).

Systemic absorption was negligible, which is of utmostimportance for oncological gynecological patients andreassuring for them and their physician. Before therapy,the mean basal plasma level of E1S was 533 pg/ml±741SD (range 22–2920). After 1 month of treatment, themean plasma level was 374 pg/ml±255 SD (81–856).The variation was not statistically significant (Wilcoxon’stest,P= 0.39).

This is more reassuring if we consider that topicalestrogen can escape into general circulation, in the first2–4 weeks of treatment, because of rapid absorptionthrough a thin atrophic vaginal mucosa and all thesepatients had a highly symptomatic vaginal atrophy. Then,absorption was reduced till it was not clinically relevantonce vaginal thickening had occurred [53,54]. Thus, ifthere was no effect after the first month, an even lesserabsorption thereafter was expected.

In this study, the only plasma estrogen measured wasestrone sulfate (E1S), but this estrogen was chosenbecause it is considered a ‘reservoir’ and an importantmarker for assessing women’s overall ‘estrogenicity.As compared with both E1 and E2 precursors, E1S ispresent at 10–50 fold higher plasma concentrations,enabling its more sensitive quantification with a betterinterassay variation. Furthermore, it is characterized bya  prolonged  half-life  that  makes  its  measurement independent of the blood sampling time and of theproblems associated with the diurnal variations of E1 andE2. Measurement of E1S with accurate and sensitivemass spectrometry makes this study interesting com-pared with previous studies carried out using an RIA assaybecause mass spectrometry has been shown to be moreaccurate and sensitive. E1S was chosen because measure-ments of serum estradiol have technical problems linkedto the difficulties of accurate determination of very lowconcentrations in postmenopausal patients [56–58]. Thisstudy was limited by the small number of patients, but itwas  very  difficult  to  enroll  oncologic  gynecologicalpatients; some of them had a contraindication for localestrogens such as endometrial cancer, and all of themwere scared to use estrogens. We chose to limit the studyto highly symptomatic patients and to assess E1S, beforeand at the end of treatment,
only in those who had usedpromestriene on a daily basis all month. In conclusion,vaginal promestriene was very effective in curing vaginaldryness and dyspareunia in oncology patients whereasplasma estrone sulfate levels did not change significantly.The efficacy and safety data were in line with previousliterature  on  promestriene.  These  results,  althoughpreliminary, helped to confirm and provide reassurancethat promestriene is a safe and effective therapy.

Evidence and reasons of the low vaginal absorption ofpromestrienePromestriene acts only in the vaginal mucosa; it does notalter the plasmatic levels of gonadotrophins or estradioland it does not stimulate the endometrium. It is not evenconverted back into estradiol. This favorable safetyprofile has been shown by both animal and humanclinical data.

In two randomized, double-blind trials, promestriene wascompared with placebo and no differences in systemicactivity were documented.

In a study comparing vaginal creams containing promes-triene and conjugated equine estrogens (CEEs), bothcreams significantly improved vulvovaginal symptomato-logy, but promestriene had significantly less impact onsystemic activity.Indeed,  promestriene  did  not  affect  the  levels  ofestradiol, FSH, or LH, whereas the CEE cream increasedestradiol (P< 0.05) and decreased both FSH (P< 0.05)and LH (P< 0.01) after 14 days.

Vaginal absorption was minimal: only 100–150 times lessthan the same dose 10 mg taken orally. Promestrienewas very poorly absorbed, less than 1%, even aftercutaneous application.

The pharmacologic peculiarities of promestriene werebecause of the presence in the molecule of estradiol of3-propyl and 17b-methyl ether groups. These changescould make it less able to penetrate the basal membrane.

The 3-propyl ether group of promestriene provided somehormone protection against hepatic degradation in a liverperfusion study.

A cross-over trial involving postmenopausal volunteersconfirmed the poor vaginal absorption of promestriene.Following vaginal administration, plasma promestrienelevels peaked between 0.2 and 0.5 ng/ml within 8 h, butthey were about 150 times greater (45–80 ng/ml) within4 h  after  oral  administration  of  the  same  dose  of10 mg.

The promestriene capsule was safe in the treatment ofpostmenopausal atrophic vaginitis in a study of 53women aged between 45 and 75 years, with more than 1year of menopause history, and postmenopausal vaginalatrophy.

Promestriene was administered by continuous therapy for20 days, and then as maintenance therapy for 8 weeks(one capsule two times per week). The levels of FSH andE2 in serum were measured and the thickness of theendometrium was determined before and after treat-ment. The routine biochemical test was used as an indexto monitor the safety. The vaginal mature index, theatrophic vaginitis evaluating score, and vaginal healthyevaluating score were determined for therapeutic effect.In the meantime, adverse effects were recorded.

During promestriene treatment, no adverse events wereobserved. Before treatment, the mean levels of FSH andE2 were 71±3 U/l and 41±18 pmol/l, and the meanthickness of endometrium was 2.4±0.9 mm. After treat-ment, the mean levels of FSH and E2 were 67±22 U/land  43±37 pmol/l,  whereas  the  mean  thickness  ofendometrium was 2.5±1.3 mm. No significant differencewas  observed  (P> 0.05).  At  the  same  time,  thetherapeutic effect was maintained: the vaginal matureindex was 42±15 before and 54±8 after treatment.The atrophic vaginitis evaluating score was 3.4±1.7before and 1.5±1.4 after treatment. Vaginal healthyevaluating score was 7.8±2.4 before and 12.0±2.4 aftertreatment. They all showed a significant difference(P< 0.01).

How to further reduce promestriene absorptionPromestriene did not show any systemic estrogeniceffects even after up to 4–6 months of therapeutic dosesin clinical studies, but its absorption could be furtherminimized by using a very low initial dose that can beincreased gradually until the minimal effective dose forindividual patients is reached.At the very beginning of the treatment, the thin atrophicvaginal  mucosa  can  better  absorb  local  estrogens,especially if it is dry and has microfissures. The minimalsystemic effect is reduced until it is not clinically relevantonce vaginal thickening has occurred.

The time to improved symptoms with topical vaginalestrogens is roughly 4 weeks with conventional doses;with very low initial doses, patients must be informedto wait for perceived benefits to increase treatmentsafety.The studies available did not indicate systemic absorp-tion in the first weeks of treatment when the transvaginalpassage was at the maximum level and using standarddoses, confirming the safety of promestriene.

Currently prescribed doses are in excess as comparedwith the minimal effective dose to cure atrophy.There is no direct relationship between improvement ofvaginal symptoms and estrogenic levels obtained in theserum after therapy.Even high promestriene dosages, two to nine times thoserecommended, administered for shorter periods (singledose to 2 weeks) did not produce significant changes inthe levels of estradiol or the gonadotrophic hormones LHor FSH or even SHBG.

Breast and endometrial effects of vaginal estrogensLow doses of topical vaginal estrogen therapy, because ofits limited systemic absorption, are believed to have littleor no effect on breasts.It has been calculated that for every doubling of E2systemic concentration, there is an overall increase in therelative risk of 1.29 (95% confidence interval 1.15–1.44;P< 0.001) to develop breast cancer. As promes-triene does not alter hormone levels, it should not modifythe risk of breast cancer.

In  patients  with  breast  cancer  who  use  aromataseinhibitors, local estrogens are precaution contraindicatedon the basis of the results of a study on only seven womentaking aromatase inhibitors with subsequent intolerableurogenital side effects treated with vaginal estradioltablets, not with promestriene. Estradiol levels increasedfrom a mean baseline level of 5 pmol/l to a mean of72 pmol/l at 2 weeks. By 4 weeks, this had decreased toless than 35 pmol/l in the majority of patients (median16 pmol/l) although significant further increases werefound in two women after 7 weeks of treatment.Other studies did not confirm these results.

There are no associations between the use of local low-potency estrogen therapy and different breast cancerhistology, ductal or lobular, in a population-based case–control study. Only the estimates for tubular cancer arenonsignificantly above unity, with no trend of increasedestimates for longer vaginal estrogen use.

The safety of local estrogens is such that they can be usedin highly symptomatic patients with breast cancer.

There is no evidence of endometrial proliferation inwomen treated for 6–24 months with topical estrogenpreparations.

The Society of Obstetricians and Gynaecologists ofCanada does not support the need for annual endometrialsurveillance or progestogen challenge in asymptomaticwomen, without bleeding.

The Cochrane reviewers recommend additional progesto-genprotectionforwomenwithauterususingvaginalestrogens only ‘if the dose used results in systemic estrogenabsorption (usually associated with doses of estradiol greaterthan 0.5 mg/daily)’.

Promestriene to improve cervical cancer early detectionPostmenopausal hormonal changes may increase atypicalcervical vaginal samples as well as ASCUS/LSIL (lowsquamous  intraepithelial  lesion)  ratio.  In  addition,because of hypoestrogenism, the squamocolumnar junc-tion may often not be visualized, thus making thecolposcopic examination unsatisfactory. The diagnosis ofASCUS in hypoestrogenic women is less likely to beassociated with dysplasia. A short-term promestrienetreatment distinguishes between benign cervical vaginalsamples  mimicking  atrophy  and  true  preneoplasticchanges and it makes the squamocolumnar junctionvisible. Moreover, it may reduce the number of endo-cervical curettage, loop excision, or cone proceduresperformed  for  women  with  inadequate  colposcopicexamination.

Safety comparative data with CEE, estriol, and estradiolThe different vaginal estrogens seem to be equallyeffective in treating vaginal atrophy but their safety isdifferent according to the Cochrane database systematicreview involving 19 randomized-controlled clinical trialsand 4162 women. In terms of safety, significant adverseeffects with CEE cream were assessed: uterine bleeding,breast pain, and perineal pain compared with tablets anda significant endometrial overstimulation with the CEEcompared with the vaginal ring.

Mass spectrometry assays of serum estradiol and estrone,which are more accurate, and sensitive, show that thevaginal CEE cream and the estradiol tablets, after only 1week of daily treatment, cause an approximately five-foldincrease in serum estradiol in postmenopausal women.Serum estradiol increases on average by 5.4-fold from 3 to17 pg/ml during the 24-h period after daily administrationof 1 g (0.625 mg) conjugated estrogens cream or 25 mcgestradiol. Serum estrone, conversely, increases 500% withCEE and 150% with estradiol. Effects are unlikely to belimited to the vagina and systemic actions are expectedafter  the  application  of  these  specific  intravaginalestrogen preparations [72]. A Doppler velocimetry studyof the periurethral vessels in stress urinary incontinencepostmenopausal women further indicated the lesser996Anti-Cancer Drugs2013, Vol 24 No 10Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

absorption of promestriene. CEE had a greater influenceon periurethral vessels and estriol had less influence,whereas promestriene had no influence on periurethralvessels [73]. Thus, after an accurate assessment of therisk/benefit ratio, vaginal low-dose, low-absorbed estrogentreatment, such as promestriene, may have played a rolein controlling vaginal atrophy even in selected andinformed hormone cancer women.

Methodological limits of this reviewMost of the literature on promestriene is from openstudies with a small number of patients, treated for a fewdays, and with a short duration of follow-up, equal to orless than 6 months. Few randomized-controlled studieswere published. After almost 40 years of use, most of theknowledge comes from the vast and long-lasting clinicalexperience of gynecologists. In fact, data from clinical andnonclinical studies indicated that no systemic estrogeniceffects have been shown both after up to 4–6 months oftherapeutic doses and even after high promestrienedosages, two to nine times those recommended adminis-tered for shorter periods of time (single dose to 2 weeks).

ConclusionPromestriene used vaginally to relieve vaginal atrophy isa locally effective estrogen that has not shown syste-mic estrogenic effects; consequently, it could be used asa first-line option for patients necessitating a minimal orideally no vaginal absorption, particularly in symptomaticcancer patients. There are few randomized-controlledstudies and most of the literature includes small, open-label, short-duration studies. After a worldwide (34countries) and long-term market experience (almost 40years), and millions of pieces prescribed, very rare sideeffects have been reported in pharmacovigilance data,whereas the effectiveness to relieve atrophy was good.Moreover, to improve its safety, a very low dose of vaginalpromestriene  could  be  used  at  the  beginning  oftreatment, starting with half or less of the usual dose,and then gradually increased till the minimum effectivedose, to reduce its already minimal vaginal absorption.

Presurgical promestriene therapy in postmenopausal women with stress urinary incontinence

OBJECTIVE:
Our study was aimed at evaluating the efficacy of therapy with promestriene, a synthetic diethyl-ether of estradiol with no distal hormonal effects, in patients undergoing surgical correction for stress urinary incontinence (SUI).
MATERIALS AND METHODS:
Ninety-eight healthy, postmenopausal women, non-users of hormone replacement therapy, with a diagnosis of SUI and vulvovaginal dystrophy, were recruited and openly randomized into two main groups. Group I (48 patients) received promestriene 10 mg daily, by vaginal capsule, for 21 days before the operation. Group II (50 patients) underwent the surgical procedure with TVT (Tension-free Vaginal Tape) directly, without pharmacological preparation. The results were collected and analyzed using SAS software (version 8).
RESULTS:
The two groups were homogeneous in terms of age, parity and body mass index. There were no significant differences between the two groups with respect to the time required to accomplish the TVT, blood loss, length of hospital stay, blood component measurements and postoperative subjective symptoms. There were slight differences postoperatively in problems during intercourse and the appearance of new genital symptoms, but again they were not shown to be statistically significant.
CONCLUSIONS:
Our results, although preliminary and subjective, confirm the efficacy of remedial surgical treatment of SUI with TVT. Preoperative administration of promestriene seems to favor trophism and vascularization of the whole muscular and fascial support of the pelvic floor and facilitates performance of the operation, but is not supported statistically.

Effect of one-month treatment with vaginal promestriene on serum estrone sulfate levels in cancer patients: A pilot study

Abstract
Vaginal promestriene was tested in gynecological cancer patients who suffered from severe vaginal dryness and dyspareunia. This form of estrogen has a low level of vaginal absorption and proved to be effective for vaginal atrophy.

Method
17 patients were treated with a 10?mg soft vaginal suppository daily for one month. Plasma levels of estrone sulfate (E1S), used as the marker of overall estrogenicity, were measured by liquid chromatography in combination with mass spectrometry.

Results
Mean E1S levels changed from 533 (22–2920) to 374 (81–856) pg/ml (p?=?0.39).

Conclusion
In highly symptomatic gynecological cancer patients the level of circulating estrone sulfate was not significantly affected by vaginal promestriene treatment overall, but a wide range of levels was noted pre and post treatment in individual patients.

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