Clinical Trials

Case History 12 - Rising FSH

I want to share my story with anyone who is despairing about ever getting pregnant.

My husband and myself had been trying to conceive for 8 years. I am now 38. We ended up having the usual investigations, where mild endometriosis was discovered. My tubes were ok, periods were very painful and heavy but otherwise I was diagnosed as unexplained. My husband's sperm was normal. I had 4 IUI's and 2 IVF's with no result.

My FSH started to rise last year and you can imagine how devastated I was when I learnt from my Consultant that I was getting old and suggested egg donation. It took my husband and myself a good while to get our heads around this but our desire to be a family won and I had two cycles done in Spain - again no result. We were battle weary at this stage and poorer!!

We started adoption proceedings three years ago and we thought this was our destiny!. Meanwhile a friend who had got pregnant through The Cork Natural Fertility clinic, using holistic treatments in Cobh, suggested I give it a go, if anything just to strengthen my body and mind after all the years of drug treatments and maybe try again with donor eggs later in the year.

From the start of treatment at Robin Hill clinic I felt I was not a number on a conveyor belt. I felt heard and listened to. I realized and friends mentioned too that it was like my old self was back. My energy, skin, hair all improved and my long standing IBS was much better. I felt the stress in my body lifting. I was sleeping like a baby again. The icing on the cake was when my period was late in August. I never dreamt I could be pregnant - I thought I couldn't be after all the years of battling with infertility. My periods could go irregular at times anyway! I don't think I am still over the shock!!! I am now 8 months pregnant with a baby girl. An absolute dream come true.

So ladies, my advice is, get your body healthy and have faith in nature. If it happened for us it could happen to you. Don't lose sight of your dreams to become a mother.

Paulus WE, Zhang M, Strehler E, El-Danasouri I, Sterzik K.

In an article published by W. Paulus, M. Zhang, I. El-Danasouri, E. Strehler and K. Sterzik titled,� Influence of Acupuncture on the Pregnancy Rate in Patients Who Undergo Assisted Reproduction Therapy,� appearing in the April 2002 issue of Fertility and Sterility, German researchers announced that they had increased the success rate by nearly 50 % in women undergoing in vitro fertilization. The researchers, led by Dr. Wolfgang E. Paulus and colleagues at the Christian-Lauritzen-Institut in Ulm, Germany, said they do not know why acupuncture works and plan to conduct more studies. �Acupuncture seems to be a useful tool for improving pregnancy rate after assisted reproductive techniques.� they wrote. �The analysis shows that the pregnancy rate for the acupuncture group is considerably higher than for the control group ( 42.5% versus 26.3%),� they wrote.

Working with a team at the Department of Chinese Medicine at Tongji Hospital in Wuhan, China, Paulus and colleagues tested 160 women undergoing in vitro fertilization. Half received the standard in vitro fertilization, while half were given acupuncture treatments before and after. �We chose acupuncture points that relax the uterus according to the principles of traditional Chinese medicine,� they wrote. They said acupuncture can affect the autonomic nervous system-involved in the control of muscles and glands-and thus, theoretically, should make the lining of the uterus more receptive to receiving an embryo.

According to the report, about 26% of women who did not receive acupuncture became pregnant, compared with nearly 43% of women who underwent the traditional Chinese therapy before and after embryo transfer. There were no differences in age, number of transferred embryos, or the number of previous cycles between the two groups of patients. In this study, women received acupuncture along the spleen and stomach channels in an attempt to relax the uterus and improve the flow of energy to this region. They also received acupuncture needles in their ears to stabilize the endocrine system.

�The results demonstrate that acupuncture therapy improves pregnancy rate,� concluded Dr. Paulus and colleagues� However, more research is needed to determine whether the higher pregnancy rate among women receiving acupuncture was due to actual physiological or psychological effects,� they added. �If these findings are confirmed, they may help us improve the odds for our IVF patients,� Dr. Sandra Carson, president-elect of the American Society of Reproductive Medicine, said in a prepared statement after the publication of this study in Fertility and Sterility.

PMID: 11937123 [PubMed - indexed for MEDLINE]

Zhang M, Huang G, Paulus WE, Sterzik K.

Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030.

The clinical effects of acupuncture on idiopathic male infertility in sperm parameter and on therapeutic results in assisted reproductive technology were investigated. 22 patients failed in intracytoplasmic sperm injection (ICSI) with idiopathic male infertility were treated with acupuncture twice weekly for 8 weeks, followed by ICSI treatment again. The sperm concentration, motility, morphology, fertilization rates and embryo quality were observed. Quick sperm motility after acupuncture (18.3% +/- 9.6%) was significantly improved as compared with that before treatment (11.0% +/- 7.5%, P < 0.01). The normal sperm ratio was increased after acupuncture (21.1% +/- 10.4% vs 16.2% +/- 8.2%, P < 0.05). The fertilization rates after acupuncture (66.2%) were obviously higher than that before treatment (40.2%, P < 0.01). There was no significant difference in sperm concentration and general sperm motility between before and after acupuncture. The embryo quality after acupuncture was improved, but the difference between them was not significant (P > 0.05). Acupuncture can improve sperm quality and fertilization rates in assisted reproductive technology.

PMID: 12658811 [PubMed - indexed for MEDLINE]

S. Siterman, F. Eltes, V. Wolfson, H. Lederman & B. Bartoov

Classic therapies are usually ineffective in the treatment of patients with very poor sperm density. The aim of this study was to determine the effect of acupuncture on these males. Semen samples of 20 patients with a history of azoospermia were examined by light microscope (LM) and scanning electron microscope (SEM), with which a microsearch for spermatozoa was carried out. These examinations were performed before and 1 month after acupuncture treatment and revealed that the study group originally contained three severely oligoteratoasthenozoospermic (OTA), two pseudoazoospermic and 15 azoospermic patients. The control group was comprised of 20 untreated males who underwent two semen examinations within a period of 2-4 months and had initial andrological profiles similar to those of the experimental group. No changes in any of the parameters examined were observed in the control group. There was a marked but not significant improvement in the sperm counts of severely OTA males following acupuncture treatment (average=0.7±1.1×106 spermatozoa per ejaculate before treatment vs. 4.3±3.2×106 spermatozoa per ejaculate after treatment). A definite increase in sperm count was detected in the ejaculates of 10 (67%) of the 15 azoospermic patients. Seven of these males exhibited post-treatment spermatozoa that were detected even by LM. The sperm production of these seven males increased significantly, from 0 to an average of 1.5±2.4×106 spermatozoa per ejaculate (Z=-2.8, P≤0.01). Males with genital tract inflammation exhibited the most remarkable improvement in sperm density (on average from 0.3±0.6×106 spermatozoa per ejaculate to 3.3±3.2×106 spermatozoa per ejaculate; Z=-2.4, P≤0.02). Two pregnancies were achieved by the IVF-ICSI procedure. It is concluded that acupuncture may be a useful, nontraumatic treatment for males with very poor sperm density, especially those with a history of genital tract inflammation.

[Article in German]

Fischl F, Riegler R, Bieglmayer C, Nasr F, Neumark J.

Our first attempt in treating subfertility by acupuncture was carried out on 28 males. The results obtained from the experiences in veterinary medicine encouraged us to attempt this type of therapy. Each patient received a total of 10 treatments for a period of three weeks. Several spermiograms were made after diagnosis subfertility. We checked spermiograms and hormone levels before and after acupuncture. Total count, concentration and motility were evaluated. In all cases we observed a statistically significant improvement of sperm quality. Having obtained these good results in our first studies, we now intend to continue acupuncture therapy in subfertile males for insemination or intercourse at the time of the ovulation of their female partners.

PMID: 6566639 [PubMed - indexed for MEDLINE]

Wolfgang E. Paulus, M.D.,[a] Mingmin Zhang, M.D.,[b] Erwin Strehler, M.D.,[a] Imam El-Danasouri, Ph.D.,[a] and Karl Sterzik, M.D.[a] Christian-Lauritzen-Institut, Ulm, Germany

Fertility And Sterility VOL. 77, No. 4, April 2002

Copyright ©2002 American Society for Reproductive Medicine Published by Elsevier Science Inc.

Received June 5, 2001; revised and accepted October 16, 2001. Reprint requests: Wolfgang E. Paulus, M.D., Christian-Lauritzen-Institut, Frauenstr. 51, D-89073, Ulm, Germany (FAX: ++49-731-9665130; E-mail: paulus@reprotox.de).

[a] Department of Reproductive Medicine, Christian-Lauritzen-Institut.

[b] Department of Traditional Chinese Medicine, Tongji Hospital, Tongji Medical University, Wuhan, People's Republic of China.

0015-0282/02/$22.00

PII S0015-0282(01)03273-3

Objective

To evaluate the effect of acupuncture on the pregnancy rate in assisted reproduction therapy (ART) by comparing a group of patients receiving acupuncture treatment shortly before and after embryo transfer with a control group receiving no acupuncture.

Design

Prospective randomized study.

Setting

Fertility center.

Patient(s)

After giving informed consent, 160 patients who were undergoing ART and who had good quality embryos were divided into the following two groups through random selection: embryo transfer with acupuncture (n = 80) and embryo transfer without acupuncture (n = 80).

Intervention(s)

Acupuncture was performed in 80 patients 25 minutes before and after embryo transfer. In the control group, embryos were transferred without any supportive therapy.

Main Outcome Measure(s)

Clinical pregnancy was defined as the presence of a fetal sac during an ultrasound examination 6 weeks after embryo transfer.

Result(s)

Clinical pregnancies were documented in 34 of 80 patients (42.5%) in the acupuncture group, whereas pregnancy rate was only 26.3% (21 out of 80 patients) in the control group.

Conclusion(s)

Acupuncture seems to be a useful tool for improving pregnancy rate after ART. (Fertil Steril: 2002;77:721- 4. ©2002 by American Society for Reproductive Medicine.)

Key Words

Acupuncture, assisted reproduction, embryo transfer, pregnancy rate

Acupuncture is an important element of traditional Chinese medicine (TCM), which can be traced back for at least 4,000 years. Acupuncture has been shown to alleviate nausea and vomiting, dental pain, addiction, headache, menstrual cramps, tennis elbow, fibromyalgia, myofascial pain, osteoarthritis, carpal tunnel syndrome, and asthma. Both physiologic and psychological benefits of acupuncture have been scientifically demonstrated in recent years.

However, so far there have been only a few serious trials concerning the use of acupuncture in reproductive medicine. Publications focus primarily on acupuncture therapy for male infertility (1, 2). Electroacupuncture may reduce blood flow impedance in the uterine arteries of infertile women (3). A positive impact of electroacupuncture on endocrinologic parameters and ovulation in women with polycystic ovary syndrome has been demonstrated (4). In addition, auricular acupuncture was successfully used in the treatment of female infertility (5). In the present study, we chose acupuncture points that relax the uterus according to the principles of TCM. Because acupuncture influences the autonomic nervous system, such treatment should optimize endometrial receptivity (6). Our main objective was to evaluate whether acupuncture accompanying embryo transfer increases clinical pregnancy rate.

Materials and Methods

This study was a prospective randomized trial at the Christian- Lauritzen-Institut in Ulm, Germany. It was approved by the ethics committee of the University of Ulm. A total of 160 healthy women undergoing treatment with in vitro fertilization (IVF; n = 101) or intracytoplasmic sperm injection (ICSI; n = 59) were recruited into the study. The age of the patients ranged from 21 to 43 (mean age: 32.5 = 4. 0 years). The cause of infertility was the same for both groups (Table 1). Only patients with good embryo quality were included in the study. Using a computerized randomization method, patients were assigned into either the acupuncture group or the control group.

Table 1

Descriptive data on acupuncture and control group (mean ± SD or total number).

Control group

Acupuncture group

Statistics

(n = 80)

(n = 80)

Age of patients (years)

32.1 ± 3.9

32.8 ± 4.1

NS

No. of previous cycles

2.0 ± 2.0

2.1 ± 2.1

NS

No. of transferred embryos

2.1 ± 0.5

2.2 ± 0.5

NS

IVF (n)

54

47

NS

ICSI (n)

26

33

NS

No. of cycles with male factor infertility

46

47

NS

No. of cycles with tubal disease

21

22

NS

No. of cycles with polycystic ovaries

2

2

NS

No. of cycles with unknown cause of infertility

11

9

NS

Endometrial thickness (mm)

9.9 ± 2.7

9.1 ± 2.4

NS

Plasma estradiol on day of embryo transfer (pg/mL)

1001 -± 635

971 ± 832

NS

Pulsatility index of uterine arteries (PI) before embryo transfer

2.00 ± 0.56

2.02 ± 0,45

NS

Pulsatility index of uterine arteries (PI) after embryo transfer

2.19 ± 0.52

2.22 ± 0,44

NS

Pregnant

21/80 (26.3%)

34/80 (42.5%)

P=.03

NS = not significant (P>.05).

Paulus. Acupuncture in ART. Fertil Steril 2002.

Ovarian stimulation, oocyte retrieval, and in vitro culture were performed as previously described (7). Transvaginal ultrasound-guided needle aspiration of follicular fluid was performed 36 to 38 hours after hCG administration. Immediately after follicle puncture, the oocytes were retrieved, assessed, and fertilized in vitro. Sperm preparation and culture conditions did not differ for either group.

In cases of severe male subfertility, ICSI was preferred, as described in the literature (8). Forty-eight hours after the IVF or ICSI procedure, embryos were evaluated according to their appearance as type 1 or 2 (good), type 3 or 4 (poor), as described in literature (9).

Just before and after embryo transfer, all patients underwent ultrasound scans of the uterus using a 7-MHz transvaginal probe (LOGIQ 400 Pro, GE Medical Systems Ultra-sound Europe, Solingen, Germany). Pulsed Doppler curves of both uterine arteries were measured by one observer. The pulsatility index (PI) for each artery was calculated electronically from a smooth curve fitted to the average waveform over three cardiac cycles.

A maximum of three embryos, in accordance with German law, were transferred into the uterine cavity on day 2 or 3 after oocyte retrieval. For embryo replacement, the patient was placed in a dorsal lithotomy position, with an empty bladder. The cervix was exposed with a bivalved speculum, then washed with culture media prior to embryo transfer. Labotect Embryo Transfer Catheter Set (Labotect GmbH, Go¨ ttingen, Germany) was used for atraumatic replacement owing to the curved guiding cannula with a ball end, allowing the set to be used reliably even with difficult anatomic conditions. The metallic reinforced inner catheter shaft al lowed safe passage through the cervical canal. When the catheter tip lay close to the fundus, the medium containing the embryos was expelled and the catheter withdrawn gently. After this procedure, the patient was placed at bed rest for 25 minutes. All oocyte retrievals and embryo transfers were performed by one examiner using the same method. The examiner was not aware of the patient's treatment group (control or acupuncture).

At the time of the embryo transfer, blood samples (10 mL) were obtained from the cubital vein. Plasma estrogen was determined by an immunometric method using the IMMULITE 2000 Immunoassay System (DPC Diagnostic Product Corporation, Los Angeles, CA).

Luteal phase support was given by transvaginal progesterone administration (Utrogest, 200 mg, three times per day; Kade, Berlin, Germany). Progesterone administration was initiated on the day after oocyte retrieval and was continued until the serum ß-hCG measurement 14 to 16 days after transfer and, in cases of pregnancy, until gestation week 8.

Each patient in the experimental group received an acupuncture treatment 25 minutes before and after embryo transfer. Sterile disposable stainless steel needles (0.25 X 25 mm) were inserted in acupuncture point locations. Needle reaction (soreness, numbness, or distention around the point = Deqi sensation) occurred during the initial insertion. After 10 minutes, the needles were rotated in order to maintain Deqi sensation. The needles were left in position for 25 minutes and then removed. The depth of needle insertion was about 10 to 20 mm, depending on the region of the body undergoing treatment. Before embryo transfer, we used the following locations: Cx6 (Neiguan), Sp8 (Diji), Liv3 (Taichong), Gv20 (Baihui), and S29 (Guilai).

After embryo transfer, the needles were inserted at the following points: S36 (Zusanli), Sp6 (Sanyinjiao), Sp10 (Xuehai), and Li4 (Hegu).

In addition, we used small stainless needles (0.2 X 13 mm) for auricular acupuncture at the following points, without rotation: ear point 55 (Shenmen), ear point 58 (Zhigong), ear point 22 (Neifenmi), and ear point 34 (Naodian). Two needles were inserted in the right ear, the other two needles in the left ear. The four needles remained in the ears for 25 minutes. The side of the auricular acupuncture was changed after embryo transfer. The patients in the control group also remained lying still for 25 minutes after embryo transfer. All treatments were performed by the same well-trained examiner, in the same way.

The primary point of the study was to determine whether acupuncture improves the clinical pregnancy rate after IVF or ICSI treatment. Student's t-test was used as a corrective against any possible imbalance between the two groups regarding the following variables: age of patient, number of previous cycles, number of transferred embryos, endometrial thickness, plasma estradiol on day of transfer, method of treatment (IVF or ICSI), and blood flow impedance in the uterine arteries (pulsatility index). Chi-square test was used to compare the two groups. All statistical analyses were carried out using the software package Stathttp://easternharmonyclinic.com/medart/graphics (Manugistics, Inc., Rockville, MD).

Results

A total of 160 patients was recruited for the study. Patients who failed to conceive during the first treatment cycle were not reentered into the study. According to the randomization, 80 patients were treated with acupuncture, and 80 patients underwent the usual therapy without acupuncture.

As Table 1 shows, there were no statistically significant differences between the two groups with respect to the following covariants: age of patient, number of previous cycles, number of transferred embryos, endometrial thickness, plasma estradiol on day of transfer, or method of treatment (IVF or ICSI). Clinical indications for ART were the same for patients of both groups. The blood flow impedance in the uterine arteries (pulsatility index) did not differ between the groups before and after embryo transfer.

The analysis shows that the pregnancy rate for the acupuncture group is considerably higher than for the control group (42.5% vs 26.3%; P=.03).

Discussion

The acupuncture points used in this study were chosen according to the principles of TCM (10): Stimulation of Taiying meridians (spleen) and Yangming meridians (stomach, colon) would result in better blood perfusion and more energy in the uterus. Stimulation of the body points Cx6, Liv3, and Gv20, as well as stimulation of the ear points 34 and 55, would sedate the patient. Ear point 58 would influence the uterus, whereas ear point 22 would stabilize the endocrine system.

The anesthesia-like effects of acupuncture have been studied extensively. Acupuncture needles stimulate muscle afferents innervating ergoreceptors, which leads to increased ß-endorphin concentration in the cerebrospinal fluid (11). The hypothalamic ß-endorphinergic system has inhibitory effects on the vasomotor center, thereby reducing sympathetic activity. This central mechanism, which involves the hypothalamic and brainstem systems, controls many major organ systems in the body (12). In addition to central sympathetic inhibition by the endorphin system, acupuncture stimulation of the sensory nerve fibers may inhibit the sympathetic outflow at the spinal level. By changing the concentration of central opioids, acupuncture may also regulate the function of the hypothalamic-pituitary-ovarian axis via the central sympathetic system (13).

Kim et al. (14) suggested that Li4 acupuncture treatment could be useful in inhibiting the uterus motility. In their rat experiments, treatment on the Li4 acupoint suppressed the expression of COX-2 enzyme in the endometrium and myometrium of pregnant and nonpregnant uteri.

Stener-Victorin et al. (3) reduced high uterine artery blood flow impedance by a series of eight electroacupuncture treatments, twice a week for 4 weeks. They suggest that a decreased tonic activity in the sympathetic vasoconstrictor fibers to the uterus and an involvement of central mechanisms with general inhibition of the sympathetic outflow may be responsible for this effect. In our study, we could not see any differences in the pulsatility index between the acupuncture and control group before or after embryo transfer. This may be due to a different acupuncture protocol and the selected sample of patients with high blood flow impedance of the uterine arteries (PI ≥ 3.0) in the Stener-Victorin et al. study.

As we could not observe any significant differences in covariants between the acupuncture and control groups, the results demonstrate that acupuncture therapy improves pregnancy rate.

Further research is needed to demonstrate precisely how acupuncture causes physiologic changes in the uterus and the reproductive system. To rule out the possibility that acupuncture produces only psychological or psychosomatic effects, we plan to use a placebo needle set as a control in a future study.

References

1. Siterman S, Eltes F, Wolfson V, Lederman H, Bartoov B. Does acupuncture treatment affect sperm density in males with very low sperm count? A pilot study. Andrologia 2000;32:31-9.

2. Bartoov B, Eltes F, Reichart M, Langzam J, Lederman H, Zabludovsky N. Quantitative ultramorphological analysis of human sperm: fifteen years of experience in the diagnosis and management of male factor infertility. Arch Androl 1999;43:13-25.

3. Stener-Victorin E, Waldenstrom U, Andersson SA, Wikland M. Reduction of blood flow impedance in the uterine arteries of infertile women with electro-acupuncture. Hum Reprod 1996;11:1314 -7.

4. Stener-Victorin E, Waldenstrom U, Tagnfors U, Lundeberg T, Lindst- edt G, Janson PO. Effects of electro-acupuncture on anovulation in women with polycystic ovary syndrome. Acta Obstet Gynecol Scand 2000;79:180 -8.

5. Gerhard I, Postneek F. Auricular acupuncture in the treatment of female infertility. Gynecol Endocrinol 1992;6:171-81.

6. Stener-Victorin E, Lundeberg T, Waldenstrom U, Manni L, Aloe L, Gunnarsson S, Janson PO: Effects of electro-acupuncture on nerve growth factor and ovarian morphology in rats with experimentally induced polycystic ovaries. Biol Reprod 2000;63:1497-503.

7. Strehler E, Abt M, El-Danasouri I, De Santo M, Sterzik K. Impact of recombinant follicle-stimulating hormone and human menopausal gonadotropins on in vitro fertilization outcome. Fertil Steril 2001;75: 332-6.

8. Palermo GD, Schlegel PN, Colombero LT, Zaninovic N, Moy F, Rosenwaks Z. Aggressive sperm immobilization prior to intracytoplasmic sperm injection with immature spermatozoa improves fertilization and pregnancy rates. Hum Reprod 1996;11:1023-9.

9. Plachot M, Mandelbaum J: Oocyte maturation, fertilization and embryonic growth in vitro. Br Med Bull 1990;46:675-94.

10. Maciocia G. Obstetrics and gynecology in Chinese medicine. New York: Churchill Livingstone, 1998.

11. Hoffmann P, Terenius L, Thoren P. Cerebrospinal fluid immunoreactive beta-endorphin concentration is increased by voluntary exercise in the spontaneously hypertensive rat. Regul Pept 1990;28:233-9.

12. Andersson SA, Lundeberg T. Acupuncture-from empiricism to science: functional background to acupuncture effects in pain and disease. Med Hypotheses 1995;45:271-81.

13. Chen BY, Yu J. Relationship between blood radioimmunoreactive beta- endorphin and hand skin temperature during the electro-acupuncture induction of ovulation. Acupunct Electrother Res 1991;16:1-5.

14. Kim J, Shin KH, Na CS. Effect of acupuncture treatment on uterine motility and cyclooxygenase-2 expression in pregnant rats. Gynecol Obstet Invest 2000;50:225-30.

Wolfgang E. Paulus, M.D.,[a] Mingmin Zhang, M.D.,[b] Erwin Strehler, M.D.,[a] Imam El-Danasouri, Ph.D.,[a] and Karl Sterzik, M.D.[a] Christian-Lauritzen-Institut, Ulm, Germany

Fertility And Sterility VOL. 77, No. 4, April 2002

Copyright ©2002 American Society for Reproductive Medicine Published by Elsevier Science Inc.

Received June 5, 2001; revised and accepted October 16, 2001. Reprint requests: Wolfgang E. Paulus, M.D., Christian-Lauritzen-Institut, Frauenstr. 51, D-89073, Ulm, Germany (FAX: ++49-731-9665130; E-mail: paulus@reprotox.de).

[a] Department of Reproductive Medicine, Christian-Lauritzen-Institut.

[b] Department of Traditional Chinese Medicine, Tongji Hospital, Tongji Medical University, Wuhan, People's Republic of China.

0015-0282/02/$22.00

PII S0015-0282(01)03273-3

Objective

To evaluate the effect of acupuncture on the pregnancy rate in assisted reproduction therapy (ART) by comparing a group of patients receiving acupuncture treatment shortly before and after embryo transfer with a control group receiving no acupuncture.

Design

Prospective randomized study.

Setting

Fertility center.

Patient(s)

After giving informed consent, 160 patients who were undergoing ART and who had good quality embryos were divided into the following two groups through random selection: embryo transfer with acupuncture (n = 80) and embryo transfer without acupuncture (n = 80).

Intervention(s)

Acupuncture was performed in 80 patients 25 minutes before and after embryo transfer. In the control group, embryos were transferred without any supportive therapy.

Main Outcome Measure(s)

Clinical pregnancy was defined as the presence of a fetal sac during an ultrasound examination 6 weeks after embryo transfer.

Result(s)

Clinical pregnancies were documented in 34 of 80 patients (42.5%) in the acupuncture group, whereas pregnancy rate was only 26.3% (21 out of 80 patients) in the control group.

Conclusion(s)

Acupuncture seems to be a useful tool for improving pregnancy rate after ART. (Fertil Steril: 2002;77:721- 4. ©2002 by American Society for Reproductive Medicine.)

Key Words

Acupuncture, assisted reproduction, embryo transfer, pregnancy rate

Acupuncture is an important element of traditional Chinese medicine (TCM), which can be traced back for at least 4,000 years. Acupuncture has been shown to alleviate nausea and vomiting, dental pain, addiction, headache, menstrual cramps, tennis elbow, fibromyalgia, myofascial pain, osteoarthritis, carpal tunnel syndrome, and asthma. Both physiologic and psychological benefits of acupuncture have been scientifically demonstrated in recent years.

However, so far there have been only a few serious trials concerning the use of acupuncture in reproductive medicine. Publications focus primarily on acupuncture therapy for male infertility (1, 2). Electroacupuncture may reduce blood flow impedance in the uterine arteries of infertile women (3). A positive impact of electroacupuncture on endocrinologic parameters and ovulation in women with polycystic ovary syndrome has been demonstrated (4). In addition, auricular acupuncture was successfully used in the treatment of female infertility (5). In the present study, we chose acupuncture points that relax the uterus according to the principles of TCM. Because acupuncture influences the autonomic nervous system, such treatment should optimize endometrial receptivity (6). Our main objective was to evaluate whether acupuncture accompanying embryo transfer increases clinical pregnancy rate.

Materials and Methods

This study was a prospective randomized trial at the Christian- Lauritzen-Institut in Ulm, Germany. It was approved by the ethics committee of the University of Ulm. A total of 160 healthy women undergoing treatment with in vitro fertilization (IVF; n = 101) or intracytoplasmic sperm injection (ICSI; n = 59) were recruited into the study. The age of the patients ranged from 21 to 43 (mean age: 32.5 = 4. 0 years). The cause of infertility was the same for both groups (Table 1). Only patients with good embryo quality were included in the study. Using a computerized randomization method, patients were assigned into either the acupuncture group or the control group.

Table 1

Descriptive data on acupuncture and control group (mean ± SD or total number).

Control group

Acupuncture group

Statistics

(n = 80)

(n = 80)

Age of patients (years)

32.1 ± 3.9

32.8 ± 4.1

NS

No. of previous cycles

2.0 ± 2.0

2.1 ± 2.1

NS

No. of transferred embryos

2.1 ± 0.5

2.2 ± 0.5

NS

IVF (n)

54

47

NS

ICSI (n)

26

33

NS

No. of cycles with male factor infertility

46

47

NS

No. of cycles with tubal disease

21

22

NS

No. of cycles with polycystic ovaries

2

2

NS

No. of cycles with unknown cause of infertility

11

9

NS

Endometrial thickness (mm)

9.9 ± 2.7

9.1 ± 2.4

NS

Plasma estradiol on day of embryo transfer (pg/mL)

1001 -± 635

971 ± 832

NS

Pulsatility index of uterine arteries (PI) before embryo transfer

2.00 ± 0.56

2.02 ± 0,45

NS

Pulsatility index of uterine arteries (PI) after embryo transfer

2.19 ± 0.52

2.22 ± 0,44

NS

Pregnant

21/80 (26.3%)

34/80 (42.5%)

P=.03

NS = not significant (P>.05).

Paulus. Acupuncture in ART. Fertil Steril 2002.

Ovarian stimulation, oocyte retrieval, and in vitro culture were performed as previously described (7). Transvaginal ultrasound-guided needle aspiration of follicular fluid was performed 36 to 38 hours after hCG administration. Immediately after follicle puncture, the oocytes were retrieved, assessed, and fertilized in vitro. Sperm preparation and culture conditions did not differ for either group.

In cases of severe male subfertility, ICSI was preferred, as described in the literature (8). Forty-eight hours after the IVF or ICSI procedure, embryos were evaluated according to their appearance as type 1 or 2 (good), type 3 or 4 (poor), as described in literature (9).

Just before and after embryo transfer, all patients underwent ultrasound scans of the uterus using a 7-MHz transvaginal probe (LOGIQ 400 Pro, GE Medical Systems Ultra-sound Europe, Solingen, Germany). Pulsed Doppler curves of both uterine arteries were measured by one observer. The pulsatility index (PI) for each artery was calculated electronically from a smooth curve fitted to the average waveform over three cardiac cycles.

A maximum of three embryos, in accordance with German law, were transferred into the uterine cavity on day 2 or 3 after oocyte retrieval. For embryo replacement, the patient was placed in a dorsal lithotomy position, with an empty bladder. The cervix was exposed with a bivalved speculum, then washed with culture media prior to embryo transfer. Labotect Embryo Transfer Catheter Set (Labotect GmbH, Go¨ ttingen, Germany) was used for atraumatic replacement owing to the curved guiding cannula with a ball end, allowing the set to be used reliably even with difficult anatomic conditions. The metallic reinforced inner catheter shaft al lowed safe passage through the cervical canal. When the catheter tip lay close to the fundus, the medium containing the embryos was expelled and the catheter withdrawn gently. After this procedure, the patient was placed at bed rest for 25 minutes. All oocyte retrievals and embryo transfers were performed by one examiner using the same method. The examiner was not aware of the patient's treatment group (control or acupuncture).

At the time of the embryo transfer, blood samples (10 mL) were obtained from the cubital vein. Plasma estrogen was determined by an immunometric method using the IMMULITE 2000 Immunoassay System (DPC Diagnostic Product Corporation, Los Angeles, CA).

Luteal phase support was given by transvaginal progesterone administration (Utrogest, 200 mg, three times per day; Kade, Berlin, Germany). Progesterone administration was initiated on the day after oocyte retrieval and was continued until the serum ß-hCG measurement 14 to 16 days after transfer and, in cases of pregnancy, until gestation week 8.

Each patient in the experimental group received an acupuncture treatment 25 minutes before and after embryo transfer. Sterile disposable stainless steel needles (0.25 X 25 mm) were inserted in acupuncture point locations. Needle reaction (soreness, numbness, or distention around the point = Deqi sensation) occurred during the initial insertion. After 10 minutes, the needles were rotated in order to maintain Deqi sensation. The needles were left in position for 25 minutes and then removed. The depth of needle insertion was about 10 to 20 mm, depending on the region of the body undergoing treatment. Before embryo transfer, we used the following locations: Cx6 (Neiguan), Sp8 (Diji), Liv3 (Taichong), Gv20 (Baihui), and S29 (Guilai).

After embryo transfer, the needles were inserted at the following points: S36 (Zusanli), Sp6 (Sanyinjiao), Sp10 (Xuehai), and Li4 (Hegu).

In addition, we used small stainless needles (0.2 X 13 mm) for auricular acupuncture at the following points, without rotation: ear point 55 (Shenmen), ear point 58 (Zhigong), ear point 22 (Neifenmi), and ear point 34 (Naodian). Two needles were inserted in the right ear, the other two needles in the left ear. The four needles remained in the ears for 25 minutes. The side of the auricular acupuncture was changed after embryo transfer. The patients in the control group also remained lying still for 25 minutes after embryo transfer. All treatments were performed by the same well-trained examiner, in the same way.

The primary point of the study was to determine whether acupuncture improves the clinical pregnancy rate after IVF or ICSI treatment. Student's t-test was used as a corrective against any possible imbalance between the two groups regarding the following variables: age of patient, number of previous cycles, number of transferred embryos, endometrial thickness, plasma estradiol on day of transfer, method of treatment (IVF or ICSI), and blood flow impedance in the uterine arteries (pulsatility index). Chi-square test was used to compare the two groups. All statistical analyses were carried out using the software package Stathttp://easternharmonyclinic.com/medart/graphics (Manugistics, Inc., Rockville, MD).

Results

A total of 160 patients was recruited for the study. Patients who failed to conceive during the first treatment cycle were not reentered into the study. According to the randomization, 80 patients were treated with acupuncture, and 80 patients underwent the usual therapy without acupuncture.

As Table 1 shows, there were no statistically significant differences between the two groups with respect to the following covariants: age of patient, number of previous cycles, number of transferred embryos, endometrial thickness, plasma estradiol on day of transfer, or method of treatment (IVF or ICSI). Clinical indications for ART were the same for patients of both groups. The blood flow impedance in the uterine arteries (pulsatility index) did not differ between the groups before and after embryo transfer.

The analysis shows that the pregnancy rate for the acupuncture group is considerably higher than for the control group (42.5% vs 26.3%; P=.03).

Discussion

The acupuncture points used in this study were chosen according to the principles of TCM (10): Stimulation of Taiying meridians (spleen) and Yangming meridians (stomach, colon) would result in better blood perfusion and more energy in the uterus. Stimulation of the body points Cx6, Liv3, and Gv20, as well as stimulation of the ear points 34 and 55, would sedate the patient. Ear point 58 would influence the uterus, whereas ear point 22 would stabilize the endocrine system.

The anesthesia-like effects of acupuncture have been studied extensively. Acupuncture needles stimulate muscle afferents innervating ergoreceptors, which leads to increased ß-endorphin concentration in the cerebrospinal fluid (11). The hypothalamic ß-endorphinergic system has inhibitory effects on the vasomotor center, thereby reducing sympathetic activity. This central mechanism, which involves the hypothalamic and brainstem systems, controls many major organ systems in the body (12). In addition to central sympathetic inhibition by the endorphin system, acupuncture stimulation of the sensory nerve fibers may inhibit the sympathetic outflow at the spinal level. By changing the concentration of central opioids, acupuncture may also regulate the function of the hypothalamic-pituitary-ovarian axis via the central sympathetic system (13).

Kim et al. (14) suggested that Li4 acupuncture treatment could be useful in inhibiting the uterus motility. In their rat experiments, treatment on the Li4 acupoint suppressed the expression of COX-2 enzyme in the endometrium and myometrium of pregnant and nonpregnant uteri.

Stener-Victorin et al. (3) reduced high uterine artery blood flow impedance by a series of eight electroacupuncture treatments, twice a week for 4 weeks. They suggest that a decreased tonic activity in the sympathetic vasoconstrictor fibers to the uterus and an involvement of central mechanisms with general inhibition of the sympathetic outflow may be responsible for this effect. In our study, we could not see any differences in the pulsatility index between the acupuncture and control group before or after embryo transfer. This may be due to a different acupuncture protocol and the selected sample of patients with high blood flow impedance of the uterine arteries (PI ≥ 3.0) in the Stener-Victorin et al. study.

As we could not observe any significant differences in covariants between the acupuncture and control groups, the results demonstrate that acupuncture therapy improves pregnancy rate.

Further research is needed to demonstrate precisely how acupuncture causes physiologic changes in the uterus and the reproductive system. To rule out the possibility that acupuncture produces only psychological or psychosomatic effects, we plan to use a placebo needle set as a control in a future study.

References

1. Siterman S, Eltes F, Wolfson V, Lederman H, Bartoov B. Does acupuncture treatment affect sperm density in males with very low sperm count? A pilot study. Andrologia 2000;32:31-9.

2. Bartoov B, Eltes F, Reichart M, Langzam J, Lederman H, Zabludovsky N. Quantitative ultramorphological analysis of human sperm: fifteen years of experience in the diagnosis and management of male factor infertility. Arch Androl 1999;43:13-25.

3. Stener-Victorin E, Waldenstrom U, Andersson SA, Wikland M. Reduction of blood flow impedance in the uterine arteries of infertile women with electro-acupuncture. Hum Reprod 1996;11:1314 -7.

4. Stener-Victorin E, Waldenstrom U, Tagnfors U, Lundeberg T, Lindst- edt G, Janson PO. Effects of electro-acupuncture on anovulation in women with polycystic ovary syndrome. Acta Obstet Gynecol Scand 2000;79:180 -8.

5. Gerhard I, Postneek F. Auricular acupuncture in the treatment of female infertility. Gynecol Endocrinol 1992;6:171-81.

6. Stener-Victorin E, Lundeberg T, Waldenstrom U, Manni L, Aloe L, Gunnarsson S, Janson PO: Effects of electro-acupuncture on nerve growth factor and ovarian morphology in rats with experimentally induced polycystic ovaries. Biol Reprod 2000;63:1497-503.

7. Strehler E, Abt M, El-Danasouri I, De Santo M, Sterzik K. Impact of recombinant follicle-stimulating hormone and human menopausal gonadotropins on in vitro fertilization outcome. Fertil Steril 2001;75: 332-6.

8. Palermo GD, Schlegel PN, Colombero LT, Zaninovic N, Moy F, Rosenwaks Z. Aggressive sperm immobilization prior to intracytoplasmic sperm injection with immature spermatozoa improves fertilization and pregnancy rates. Hum Reprod 1996;11:1023-9.

9. Plachot M, Mandelbaum J: Oocyte maturation, fertilization and embryonic growth in vitro. Br Med Bull 1990;46:675-94.

10. Maciocia G. Obstetrics and gynecology in Chinese medicine. New York: Churchill Livingstone, 1998.

11. Hoffmann P, Terenius L, Thoren P. Cerebrospinal fluid immunoreactive beta-endorphin concentration is increased by voluntary exercise in the spontaneously hypertensive rat. Regul Pept 1990;28:233-9.

12. Andersson SA, Lundeberg T. Acupuncture-from empiricism to science: functional background to acupuncture effects in pain and disease. Med Hypotheses 1995;45:271-81.

13. Chen BY, Yu J. Relationship between blood radioimmunoreactive beta- endorphin and hand skin temperature during the electro-acupuncture induction of ovulation. Acupunct Electrother Res 1991;16:1-5.

14. Kim J, Shin KH, Na CS. Effect of acupuncture treatment on uterine motility and cyclooxygenase-2 expression in pregnant rats. Gynecol Obstet Invest 2000;50:225-30.

(1) The effectiveness of a Chinese formula called 'Tian gui fang' in comparison with metformin was tested on patients with polycystic ovarian syndrome [PCOS]. The patients were divided into two groups and either Tian gui fang or metformin was administered for three months. After treatment, 4 out of the 8 patients on metformin had restoration of menstrual cyclicity, and two of them had a double phase BBT. The testosterone levels had decreased. No other measures changed. In the group that received the Chinese medicine, 6 patients out of 8 had a restored cycle as well as a double phase BBT. Testosterone and the body mass index (BMI) decreased significantly. The authors conclude that both therapies can induce ovulation but that Chinese herbal medicine has a higher efficacy in restoring ovulation and normal BBT measures.

Hou J, Yu J, Wei M. '[Study on treatment of hyperandrogenism and hyperinsulinism in polycystic ovary syndrome with chinese herbal formula 'tian gui fang]'. Zhongguo Zhong Xi Jie he Za Zhi. 2000; 20 (8):589.

(2) The effectiveness of a Chinese herbal formulary was tested on patients with high LH levels due to polycystic ovary syndrome. Eight weeks of treatment with Chinese herbal medicine significantly reduced plasma LH.

Ushiroyama T, Ikeda A, Sakai M, Hosotani T, Suzuki Y, Tsubokura S, Ueki M. 'Effects of unkei-to, an herbal medicine, on endocrine function and ovulation in women with high basal levels of luteinizing hormone secretion.' J Reprod Med. 2001 May; 46(5):451-6.

(3) In Japan, a Chinese herbal formulary was tested on patients with polycystic ovarian disease [PCOD] to find an effective treatment without side effects that could be used instead of clomiphene citrate or gonadotropin therapy. After a course of treatment, the FSH/ LH ratio had significantly decreased, and the ovulatory rate was 70.6%. Serum testosterone did not change during treatment. The authors conclude that the Chinese formula may be useful for the treatment of anovulation in PCOS patients.

Sakai A, Kondo Z, Kamei K, Izumi S, Sumi K. 'Induction of ovulation by Sairei-to for polycystic ovary syndrome patients.' Endocr J. 1999 Feb; 46(1):217-20.

(4) A case study from Taiwan discusses the effectivetreatment of premature ovarian failure using Chinese herbal medicine. Clomiphene citrate therapy over 8 months had not changed the FSH and LH levels from the postmenopausal range. A course of 4 months treatmentwith Chinese herbal medicine based on Zuo gui wan induced an ovulation, and the patient fell pregnant. The authors conclude that Chinese herbal medicine can restore ovarian function effectively and promptly andoffers another option for treating infertility in patients withpremature ovarian failure.

Chao SL, Huang LW, Yen HR. 'Pregnancy in premature ovarianfailure after therapy using Chinese herbal medicine. A case study.'Chang Gung Medical Journal 2003 Jun; 26(6): 449-52.

(5) At Shanghai medical university, the effectiveness ofChinese medical herbs from the category of yin supplementing weretested on 35 patients with polycystic anovulation. The patients were treated for three months, and a variety of tests were carried outbefore and after the course of treatment. Testosterone levels lowered significantly. In 59.7% of patients and a regular cycle was restablished. 41.2% of women became pregnant. The authors conclude that Kidney Yin nourishing herbs could provide a good microcircumstance forovarian follicular growth, which results in ovulation and pregnancy.

Zhou LR, Yu J. [Clinical observation on treatment ofhyperinsulinemia and hyperandrogenism anovulatory patient withreplenishing kidney-yin drugs] Zhongguo Zhong Xi Yi Jie He Za Zhi. 1996Sep; 16(9): 515-8.

(6) Hachimijiogan, a Chinese herbal formulary (Liu wei dihuang wan + rou gui, yin yang huo, huang qi), was shown in one study to benefit female infertility due to pituitary dysfunction. Two infertile women (one with and one without a pituitary adenoma) who were resistant to medical treatment, were given Hachimijiogan which subsequently reduced the serum prolactin level, and resulted in a normal ovulatory cycle and pregnancy, without side effects.

Usuki S; Kubota S; Usuki Y. Treatment with hachimijiogan, anon-ergot Chinese herbal medicine, in two hyperprolactinemic infertilewomen'. Acta Obstet Gynecol Scand 1989, 68 (5) p475-8.

(7) In another study looking at pituitary dysfunction causinginfertility, 27 women were given the same formulae as discussed above.6 of the women had amenorrhea. In 15 patients, the prolactin levelsdropped to a healthy range, and remained low 6 months after the courseof treatment. Four patients with amenorrhea ovulated. Eleven patientsconceived and delivered a healthy baby. In three women, the prolactinlevel did not lower. The authors conclude that a modification of Liuwei di huang wan can be a safe and effective treatment for hyperprolactinemic women.

Usuki S, Usuki Y. 'Hachimijiogan treatment is effective in themanagement of infertile women with hyperprolactaemia orbromocriptine-resistant hyperprolactaemia.' American Journal of ChineseMedicine 1989; 17 (3-4):225-41.

(8) In one study of female infertility, 53 patients withluteal phase defect (LPD) were treated with different Chinese medicinalherbs at different phases of menstrual cycle. The patients were treatedfor three menstrual cycles and there was significant improvement in theluteal phase of endometrium, and a tendency for normalization of thewave forms and its amplitude after the treatment. The findings suggested that Chinese herbal medicines are capable of replenishing the Kidney and regulate the hypothalamus-pituitary-ovarian axis and thus improve the luteal function. Among the 53 cases, 22 (41.5%) conceivedbut 68.18% of them required other measures to preserve the pregnancy.

Zhang HY; Yu XZ; Wang GL Preliminary report of the treatment ofluteal phase defect by replenishing kidney. An analysis of 53 cases.Zhongguo Zhong Xi Yi Jie He Za zhi Aug 1992, 12 (8) p473-4, 452-3.

(9) Women with normal menstrual cycles but low basal body temperature and progesterone levels (luteal insufficiency) were effectively treated with a Chinese herbal formulary called Dang guishao yao tang, with no observed side effects.

Usuki S, Higa TN, Soreya K. 'The improvement of lutealinsufficiency in fecund women by tokishakuyakusan treatment'. Am J ChinMed. 2002; 30(2-3):327-38.

Two studies are of interest in addition to the very excellent book suggested by Attilo.

One is by Elisabet Stener Victorin the other by Paulus. You can find links to both and other articles at www.aborm.org/research, the website for the Advisory Board of Oriental Reproductive Medicine.

The Stener Victorin article describes a protocol for reducing the pulsatility index in uterine arteries, which increases uterine blood flow.

I often treat women weekly for six weeks before the transfer, and have seen the pulsatility index go from 5 (unfavorable) to 1.9 (favorable). I have found that the exact protocol is not necessary (the protocol calls for e stim. I have had good results with needling and moxa.) Some sources suggest 3 mos of prior treatment for optimal results. Danish research in 2006 suggested benefit form just one treatment prior to transfer.

Valerie Hobbs, Dipl. OM.

Recent Research on Acupuncture & IVF

Paulus WE, Zhang M, Strehler E, El-Danasouri I, Sterzik K.

In an article published by W. Paulus, M. Zhang, I. El-Danasouri, E. Strehler and K. Sterzik titled,� Influence of Acupuncture on the Pregnancy Rate in Patients Who Undergo Assisted Reproduction Therapy,� appearing in the April 2002 issue of Fertility and Sterility, German researchers announced that they had increased the success rate by nearly 50 % in women undergoing in vitro fertilization. The researchers, led by Dr. Wolfgang E. Paulus and colleagues at the Christian-Lauritzen-Institut in Ulm, Germany, said they do not know why acupuncture works and plan to conduct more studies. �Acupuncture seems to be a useful tool for improving pregnancy rate after assisted reproductive techniques.� they wrote. �The analysis shows that the pregnancy rate for the acupuncture group is considerably higher than for the control group ( 42.5% versus 26.3%),� they wrote.

Working with a team at the Department of Chinese Medicine at Tongji Hospital in Wuhan, China, Paulus and colleagues tested 160 women undergoing in vitro fertilization. Half received the standard in vitro fertilization, while half were given acupuncture treatments before and after. �We chose acupuncture points that relax the uterus according to the principles of traditional Chinese medicine,� they wrote. They said acupuncture can affect the autonomic nervous system-involved in the control of muscles and glands-and thus, theoretically, should make the lining of the uterus more receptive to receiving an embryo.

According to the report, about 26% of women who did not receive acupuncture became pregnant, compared with nearly 43% of women who underwent the traditional Chinese therapy before and after embryo transfer. There were no differences in age, number of transferred embryos, or the number of previous cycles between the two groups of patients. In this study, women received acupuncture along the spleen and stomach channels in an attempt to relax the uterus and improve the flow of energy to this region. They also received acupuncture needles in their ears to stabilize the endocrine system.

�The results demonstrate that acupuncture therapy improves pregnancy rate,� concluded Dr. Paulus and colleagues� However, more research is needed to determine whether the higher pregnancy rate among women receiving acupuncture was due to actual physiological or psychological effects,� they added. �If these findings are confirmed, they may help us improve the odds for our IVF patients,� Dr. Sandra Carson, president-elect of the American Society of Reproductive Medicine, said in a prepared statement after the publication of this study in Fertility and Sterility.

PMID: 11937123 [PubMed - indexed for MEDLINE]

2007-01-30 - Bioforce AG

GHENT, NY � A randomized, double-blind study comparing Arnica Gel to 5% Ibuprofen Gel evaluated the Arnica Gel to be more effective by the patients and their doctors. Rheumatology International, a prestigious peer-reviewed medical journal will be reporting this study shortly. 1

This also marks the first time a Bioforce AG product has been studied in a head-to-head comparison with a known OTC counterpart.

The study of 204 individuals with multiple osteoarthritis in the fingers was performed from May 2003 until March 2004 by 20 medical doctors (12 general practitioners, six rheumatologists and two specialists in general medicine) in Switzerland. The study used detailed patient questionnaires for first visit and second/last visit, three weeks later. Each group, the arnica gel group and the ibuprofen gel group, applied the product three times daily to affected finger joints.

�Arnica gel was shown to be as effective as 5% ibuprogen gel, and was equally well tolerated,� says Eileen Sheets, managing director of Bioforce USA, which recently launched Arnica Rub in the U.S. �In addition, the arnica gel was evaluated as more effective by the patients and their doctors. This is great news as far as instilling consumer confidence, as well as stimulating repeat purchases for retailers.�

Sheets continues, �Although ibuprofen is an established and highly effective active substance, it is an NSAID, which is known to cause certain sensitivities in some individuals over a long period of use. Arnica has had a safe history of use as a topical product by millions of people. This study shows that there is a solid, efficacious choice out there for people who do not want to use a NSAID topical.�

In addition, this study was planned and performed according to strict international guidelines for studies of multiple osteoarthritis of the fingers (OARS; Osteoarthritis Research Group International), EMEA (European Agency for the Evaluation of Medicinal Products) guidelines for controlled studies and their statistical evaluation, as well as according to GCP Good Clinical Practice rules. This is the first study to be performed according to these strict guidelines. This is the very first study looking at this condition to be performed according to these strict guidelines.

This follows the recent news that Bioforce AG�s Arnica Gel was the first botanical product to be granted registration by the Medicines and Healthcare products Regulatory Agency under the European Directive on traditional herbal medicinal products.

1 Reto Widrig, Andy Suter, Reinhard Saller, J�rg Melzer. Choosing between NSAID and arnica for topical treatment of hand osteoarthritis in a randomised, double-blind study. Rheumatol Int DOI 10.1007/s00296-007-0304-y

Contact: Lisa Schofield (908) 216-8500