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Probiocs Innovave Strategy

for Beer Vaginal Health

At an evening symposium held by the Obstetrical & Gynaecological Societyof Hong Kong on October 22, 2009, Professor Gilbert Donders from Belgium

discussed the challenges of treang and prevenng recurrence of local vaginal

infecons, including bacterial vaginosis, candida vaginis and trichomoniasis.

He explained the importance of maintaining or restoring a normal vaginal ora

dominated by lactobacilli, and explored the role of probiocs containing viable

lactobacilli, like Gynoor (DKSH), in the management of vaginis, parcularly as

adjuvant therapy to improve outcomes and reduce the risk of recurrence.

Probiocs as an Alternave Treatment for Vaginis

Professor Gilbert GG DondersDepartment of Obstetrics and GynaecologyInfecous Diseases in OB/GYNH Hart Kliniek TienenUniversity Hospital Gasthuisberg LeuvenUniversity of LeigeLeige, Belgium

The three most frequently occurring vaginal disorders worldwide are trichomoniasis, candidavaginis and bacterial vaginosis (BV). However, other condions that are also important to considerinclude aerobic vaginis (AV), cytolyc vaginosis and mixed infecons.

Despite the availability of eecve anbioc treatments, the high recurrence rate of local vaginalinfecons shows that the management of these prevalent condions needs to be improved. Many

paents wish to avoid taking repeated courses of anbiocs, which are oen associated withunpleasant side eects and potenally lead to pathogen resistance problems. Improving clinical

outcomes for women with vaginis starts with a good understanding of the healthy vaginalecosystem.

Understanding the vaginal ecosystemThe vaginal mucosa is composed of basal cells, parabasal cells, intermediate cells

and supercial epithelial cells (Figure 1), which are the cells that desquamateduring a vaginal smear. In healthy women, the vaginal epithelium is lined with

a microora ecosystem predominated by lactobacilli. These lactobacilli requirean acidic environment (pH 4.0 4.5) and they help maintain this acidity

by producing lactate (lacc acid). The lactobacilli convert glycogenreleased from desquamang supercial cells into lactose and then

lactate to lower the vagina pH. They also produce bacteriocidalcompounds, including hydrogen peroxide, and compete

with other bacteria for adhesion to the epithelial cells,thus protecng against an overgrowth of pathogenic

bacteria. Professor Donders explained that a

healthy full-thickness epithelium is essenalfor this ecosystem to operate opmally, as

the lactobacilli require an adequatesupply of glycogen from the

proliferaon, maturaonand desquamaon of

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supercial cells. Thus,the other factor essenal

to a healthy vaginalecosystem is an adequate

local oestrogen level (Figure 1).

Grading disturbances in thevaginal microora

Professor Donders emphasized that a

40x magnicaon phase-contract micro-scope is an essenal tool for physicians

treang women with suspected vaginal infec-on. Preparing a vaginal smear slide and using

simple microscopy techniques can quickly pro-vide a great deal of informaon about the case,

he said. Lactobacillary grades (LBG) can be deter-mined using simple phase-contract microscopy of

wet mounts in the clinic. The grading categories are: Grade I (normal) predominance of lactobacilli

without other bacteria Grade IIa (intermediate) predominantly lactobacilli

but evidence of other bacteria Grade IIb (intermediate) lactobacilli present but

outnumbered by many other bacteria (eg, cocci) Grade III (abnormal) no lactobacilli, many pathogenic

bacteria

Increasing LBG (LBG I, IIa, IIb and III) has been shown tobe directly correlated with increasing vaginal pH andinversely correlated with lactate concentraons.1In addion,increasing disturbance of the lactobacillary ora was highlycorrelated with the presence of genital micro-organisms,including Gardnerella vaginalis, Trichomonas vaginalis,Gram posive cocci (eg, enterococci) and Gram negave rods(eg, Escherichia coli).

Lactobacillary grading using a wet mount and phase-contrastmicroscopy is the rst invesgaon Professor Donders usesclinically; if the vaginal ecosystem is shown to be disturbed,diagnosis of the infecon can then be performed. He en-couraged the audience of clinicians to use microscopy intheir daily clinical pracce.

Bacterial vaginosis and aerobic vaginisBV is characterized by a 100- to 1,000-fold increasein pathogenic bacteria accompanied by a substanal

decrease in lactobacilli concentraons. However, thisshi in the vagina ora is not associated with leukocyteinltraon, inammaon, pain, itching, dyspareunia,vaginal redness or oedema. BV is not an inammatorycondion; it can be viewed as an ecological disorder,explained Professor Donders.

A diagnosis of BV according to Amsel involves iden-caon of three of the following four criteria: Homogeneous grey watery discharge Fishy smell (increased aer menses or

sexual intercourse)

pH >4.5 clue cells on microscopy

Using these criteria and microscopy, BVcan be diagnosed successfully during

the paent consultaon.

High recurrence rates are typical for BV,2 and may be theresult of the development of a therapy-resistant biolm onthe vaginal epithelium. This is my major point it is nottreatment of BV, but prevenon of recurrences of BV that is

the main issue for clinicians, Professor Donders commented.For recurrent BV, paents may want to use natural drugslike probiocs, rather than repeve courses of anbiocs,with their potenal for side eects and resistance inducon.

Aerobic vaginis (AV) is characterized by smears that aredecient in lactobacilli, posive for cocci and parabasalepithelial cells, and/or posive for vaginal leukocytes.3 Thepresence of parabasal cells indicates damage and/or thinningof the vaginal epithelium (Figure 2). Clinical ndings includegenital inammaon, yellow discharge, vaginal dyspareuniaand vaginal ulceraon. Aerobic pathogens including group Bstreptococci, E coliandStaphylococcus aureusare frequentlycultured.

Abnormal vaginal ora and pregnancyThe relaonship between abnormal vaginal ora (AVF) inearly pregnancy and adverse pregnancy outcomes, specicallyincreased risk of preterm delivery (PTD), has been clearlyestablished.4,5However, using metronidazole to treat pregnantwomen with asymptomac BV or trichomoniasis has shownno benet for prevenng PTD; in fact, metronidazole mayincrease the risk.6-8

Professor Donders and his colleagues have invesgated

the relaonship between AVF and PTD further to determinewhich subtypes pose the most risk in pregnancy.5,9 Hisprospecve studies have shown that full-blown BV in therst trimester has less impact on pregnancy outcome thanintermediate types of AVF,5 and that AVF, coccoid-typeAV, staphyloid AV and paral BV are the most importantpredictors of PTD.9Another recent study has shown that AVbefore the 17thweek of gestaon is correlated with placentalhistological inammaon and funisis.10

These studies show that other types of AVF, such as AV,paral BV and mixed infecons, may be more dangerous in

early pregnancy than BV. In addion, metronidazole is not theideal treatment for all women with AVF, and certainly not inpregnancy. Hence, broader and more aspecic therapies maybe needed for AVF in pregnancy, such as clindamycin and/orprobiocs, although clinical studies will be needed to supportsuch regimens.

Figure 1. The essenal elements of a healthy vaginal

ecosystem

pH=4.34.5

Estrogens

Proliferaton

Glycogen

Lactose

Lactate

Acidificaton

Lactobacilli

H2O2 Adhesion

Superficial cells

Intermediate cells

Parabasal cells

Basal cells

Mucosa

l

l

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The role of therapeuc probiocs in vaginisProfessor Donders outlined the desirable properes oftherapeuc lactobacilli as: High adhesion to the vaginal epithelium to eecvely

compete with pathogenic bacteria L gasseri, L brevis, L acidophilusandL rhamnosus

display strong epithelial adhesion Anbacterial acvity, via producon of lacc acid,

bacteriocins and hydrogen peroxide Biosurfactants and co-aggregaon of bacteria to ensure

destrucon of the biolm

Gynoor vaginal tablets are a therapeuc lactobacillipreparaon containing 0.03 mg estriol and more than 100million viable L acidophilus. Estriol is included to smulateproliferaon and maturaon of the vaginal epithelium, whichis important to support the growth and survival of lactobacilli.The L acidophilusKS 400 strain included in the product is ofhuman origin and has been shown to have the properesdesirable for therapeuc vaginal use. It promotes a lowvaginal pH through fermentaon of lactose and glycogen tolacc acid, is a strong producer of hydrogen peroxide anddisplays compeve adherence to epithelial cells.

In vitro experiments with L acidophilus KS 400 havedemonstrated its ability to produce lacc acid and rapidlyreduce the pH of the culture medium,11produce hydrogenperoxide,11 and inhibit the growth of pathogenic micro-organisms including G vaginalis, Prevotella brevia, E coli,

S aureus and Candida albicans (Figure 3).12,13 L acidophilusKS 400 was also shown to reduce adherence of G vaginalis,P breviaand E colito epithelial cells in culture.13

Treatment in the acute sengA small (n=32) mulcentre, randomized, placebo-controlled,clinical trial examined the ecacy of Gynoor (1-2 tablets for6 days) for treatment of BV, including intermediate/paral BVcases.14The cure rate (dened as 1 of the four Amsel clinicalcriteria posive) 2 weeks aer the start of therapy was 77% inthe Gynoor group and 25% in the placebo group (p5.0

l

l

ll ll

1010

108

106

104

102

101Colon

yformingunits/mL

S aureus E coli

IH11128

G vaginalis P bivia C. albicans

Control

Plus L acidophilusKS 400

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therapy.24The primary outcome of the study was the eecton the Normal Flora Index (NFI), which comprises numbers

of lactobacilli, pathogenic micro-organisms, leukocytes andvaginal pH. This was used to assess the eect on restoraon ofthe normal vaginal microora. Follow-up visits occurred 3 to7 days and 4 to 6 weeks aer the end of the adjuvant therapy.

At both follow-up visits, the NFI had increased signicantlymore in the Gynoor group than the control group (p=0.002and p=0.006, respecvely) (Figure 4).24 In addion, at thesecond follow-up, the relapse rate was lower in the Gynoorgroup than the placebo group, although the dierence was notstascally signicant (Figure 4). Thus, Gynoor signicantlyenhanced restoraon of the vaginal ora aer an-infecvetreatment for vaginis.

Professor Donders said that the available evidence forusing lactobacilli probiocs as adjuvant therapy in vaginisshows that, in this seng, probiocs have a prominentrole in enhancing the eect of anbioc treatment, andprevenng recurrences of BV and emergence of candidiasisand other types of vaginis. He also remarked that lactobacilliprobiocs have a role in the treatment of atrophic vaginis inmenopausal paents. However, paents need to understandthat repeve courses are required. Due to its uniqueproperes, Gynoor promises to be a prime candidate forthese applicaons, he concluded.

ConclusionProbiocs may have a role in the treatment of BV when an-biocs are contraindicated, although repeated applicaonsmay be necessary. The aspecic acons of lactobacilli probiot-ics mostly likely provide coverage against AV, paral BV andmixed AV/BV, which can be dicult to treat successfully withtradional therapy. The largest role for lactobacilli probiocsis in the prevenon of recurrence in paents with recurrentBV and candida, through restoraon of the normal vaginalmicroora. The role of these agents in the prevenon of preg-nancy complicaons warrants invesgaon.

Q&A sessionQ Is Gynoor safe for use in paents with oestrogen-

dependent cancers?

Professor Donders: Denitely. The dose of estriol is only

0.03 mg, which is very low. It is 30 meslower than the dose in preparaons usedto treat vaginal dryness, and we use thoseregularly in such paents. The intravaginaladministraon ensures that serum levels ofestriol are almost zero. I use Gynoor for youngwomen, older women, and in pregnancy; it is safefor all these women.

Q If Gynoor is safe in hormone-dependent

tumours, why does the product informaon list it as

a contraindicaon?

Professor Donders: Gynoor has been in the market formany years, and this contraindicaon is a le-over ofthe way drugs were classied. If a drug was categorised asa hormone, it was automacally listed as contraindicaonin hormone-related cancers. But over the years, we havelearned that estriol has no eect on breast cancers. Ibelieve that this contraindicaon should be removed fromthe drug leaet, but obviously this will require the supportof appropriate clinical studies.

Q What stain should be used when performing

microscopy examinaon of smears?

Professor Donders: No stain is needed. The important thing isto use a phase-contrast microscope, not a light microscope.The superiority of phase contrast has even been proven in acontrolled trial.

Q Is sexual acvity contraindicated while using Gynoor?

Professor Donders: It is probably beer to avoid sexualacvity during any intravaginal drug therapy, but ifsexual acvity is planned, it would be best to administerGynoor aerwards. But sexual acvity is not a formalcontraindicaon.

References

1.Donders GG, et al. Am J Obstet Gynecol 2000;182:872-878. 2.Bradshaw CS, et al. J InfectDis 2006;193:1478-1486. 3. Donders GG, et al. Br J Obstet Gynaecol 2002;109:34-43.4. Donders G, et al. Am J Perinatol 1993;10:358-361. 5. Donders G, et al. Prenat NeonatMed 1998;3:588-593. 6. Carey JC, et al. N Engl J Med 2000;342:534-540. 7.Klebano MA,et al. N Engl J Med 2001;345:487-493. 8.Odendaal HJ, et al. South Afr Med J 2002;92:231-234. 9.Donders GG, et al. Br J Obstet Gynaecol 2009;116:1315-1324. 10. Rezeberga D, etal. Acta Obstet Gynecol Scand 2008;87:360-365. 11.Schoeni M, et al. SAZ 1988;126:139-142 [in German]. 12. Kanne B, et al. Jatros/Gynaekologie 1986;2:11-28 [in German].13. Data on le; DKSH. 14. Parent D, et al. Arzneimielforschung 1996;46:68-73.15. Anukam KC, et al. Microbes Infect 2006;8:2772-2776. 16.Halln A, et al. Sex TransmDis 1992;19:146-148. 17. Fredricsson B, et al. Gynecol Obstet Invest 1989;28:156-160.18. Anukam K, et al. Microbes Infect 2006;8:1450-1454. 19. Neri A, et al. Acta ObstetGynecol Scand 1993;72:17-19. 20. Shalev E, et al. Arch Fam Med 1996;5:593-596.21.Reid G, et al. FEMS Immunol Med Microbiol2001;32:37-41. 22.Reid G, et al. FEMSImmunol Med Microbiol 2003;35:131-134. 23. Reid G. J Med Food 2004;7:223-228.24.zkinay, et al. Br J Obstet Gynaecol2005;112:234-240. 25.Larsson PG, et al. BMC

Womens Health2008;8:3.

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Figure 4. Gynoor adjuvant therapy improved the NFI and

reduced relapse rate aer treatment for vaginis24

C1 C2 Gynoflor Placebo

Normal Flora Index (NFI)

2.0

1.8

1.6

1.4

1.2

1.0

0.8

0.4

0.4

0.2

0

16

14

12

10

8

6

4

2

0

Relapse rate

NFIchangefrom

baseline

%relaps

e

12.65%

7.9%

Gynoflor

Placebo

C1, follow-up at 3-7 days post-therapy; C2, follow-up at 4-6 weeks post-therapy