Dr. Lindgren is a Clinical Teaching Fellow, Department of Clinical Medicine, Ross University School of Medicine, Commonwealth of Dominica, West Indies. Dr. Selfridge is Professor and Chair, Department of Clinical Medicine, Ross University School of Medicine, Commonwealth of Dominica, West Indies.

Dr. Lindgren and Dr. Selfridge report no financial relationships relevant to this field of study.

SYNOPSIS: Acupuncture as an adjunctive therapy for treating infertility in Chinese women with polycystic ovary syndrome receiving clomiphene citrate or placebo offered no benefit over sham acupuncture.

SOURCE: Wu XK, Stener-Victorin E, Kuang HY, et al. Effect of acupuncture and clomiphene in Chinese women with polycystic ovary syndrome. JAMA 2017;317:2502-2514.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder that causes infertility in women of reproductive age.¹ It is characterized by ovulatory dysfunction, excess androgen production and associated manifestations, and polycystic ovaries. The etiology remains unknown. Prevalence estimates vary and range from 2.2% to as high as 26%, depending on which diagnostic inclusion criteria are used.¹

Although clomiphene citrate is a first-line treatment for anovulation and infertility related to PCOS,² investigations of alternative methods to treat infertility in women with PCOS have been ongoing. A Cochrane Review found insufficient evidence to support the use of acupuncture for the treatment of ovulation disorders in women with PCOS, despite some individual trials that demonstrated acupuncture as effective for ovulation induction.³ For example, investigators in one study concluded that higher ovulation frequency occurred in women with PCOS receiving repeated acupuncture treatments.⁴ Studies showing benefit have had methodologic flaws or have been underpowered, preventing sufficient statistically significant evidence to change clinical management. Wu et al devised an adequately powered trial to investigate the effects of acupuncture as an adjunct therapy with clomiphene on live birth rates in Chinese women with PCOS and infertility.

The PCOS Acupuncture and Clomiphene Trial (PCOSAct) was a randomized, placebo-controlled, multicenter trial that included patients at 21 sites in the National Clinical Trial Base of Chinese Medicine in Gynecology from Mainland China. This 2 × 2 factorial trial was designed to examine the effects of active or sham acupuncture in combination with clomiphene or placebo to determine the effects on live births in Chinese women diagnosed with PCOS. Lacking strong preliminary data on live birth after acupuncture, 10% was chosen as the minimal clinically detectable difference likely to change clinical practice.

The investigators calculated that 1,000 women would need to be enrolled in the study based on the following assumptions: a 25% live birth rate with both active interventions; a 15% live birth rate with one active and one control intervention; a 5% live birth rate with both control interventions; an 80% power at a significance level of P ≤ 0.05; and a 10% dropout rate. The investigators screened 4,645 women with PCOS and determined 1,000 participants were eligible for inclusion. These participants were randomly assigned and placed in a 1:1:1:1 ratio into four intervention groups: active acupuncture plus clomiphene, sham acupuncture plus clomiphene, active acupuncture plus placebo, and sham acupuncture plus placebo. The assignments were double-blinded to everyone except the acupuncturists, who knew if they were delivering active or sham acupuncture.

Both active and sham acupuncture treatments were administered for 30 minutes twice a week, for a maximum of 32 treatments. Active acupuncture points were located in the abdominal and leg muscles associated with known autonomic innervation of the ovaries and the uterus according to traditional Chinese medicine, as well as in the hands and head. Manual and low-frequency electrical stimulation of the needles was applied in the active acupuncture treatments. In the sham acupuncture protocol, four needles were inserted superficially (less than 5 mm) without manual stimulation, one in each shoulder and upper arm at non-acupuncture points. The four needles were attached to electrodes and the acupuncturist simulated switching on the stimulator, mimicking the active acupuncture protocol, although no electrical stimulation actually was delivered.

For the medication protocol, subjects were given initial oral doses of clomiphene 50 mg or placebo between days 3 and 7 of the menstrual cycle. In patients with irregular menses and without recent menstruation, the researchers induced withdrawal bleeding with medroxyprogesterone acetate (5 mg/d) for 10 days. These patients also took clomiphene or placebo between days 3 and 7 of active bleeding. Doses of oral medication or placebo were increased by one pill in the absence of ovulation or maintained in the presence of ovulation. The maximum dosage did not exceed 150 mg per day or 750 mg per cycle. In the absence of conception, the protocol was repeated for a maximum of four menstrual cycles. Patients were instructed to have regular intercourse every two to three days, and pregnancy and ovulation were ascertained by weekly monitoring of urinary human chorionic gonadotropin and serum progesterone levels. Pregnant patients were followed within the study with ultrasonography every two weeks until fetal heart motion was visible, then referred for routine obstetric care. Birth outcomes for these patients were obtained from their obstetrical records.

The primary outcome was live birth, defined by the authors as 20 weeks’ gestation or later. See Table 1 for a summary of results. There were 69 live births (29.4%) in 235 patients receiving active acupuncture plus clomiphene, 66 (28.0%) in 236 patients with sham acupuncture plus clomiphene, 31 (13.9%) in 223 patients with active acupuncture plus placebo, and 39 (16.8%) in 232 patients with sham acupuncture plus placebo. Since no significant effect was noted on live births between clomiphene with and without active acupuncture (P = 0.39), the authors examined the main effects of clomiphene and active acupuncture. Clomiphene treatment was associated with significantly higher live birth rates than placebo treatment: 135 of 471 (28.7%) for clomiphene vs. 70 of 455 (15.4%) for placebo, a difference of 13.3% (95% confidence interval [CI], 8.0-18.5%). The live birth rate was not significantly different between the groups treated with active and sham acupuncture: 100 of 458 (21.8%) for active acupuncture vs. 105 of 468 (22.4%) for sham acupuncture, a difference of -0.6% (95% CI, -5.9% to 4.7%). Adverse events also were examined, as were quality-of-life scores using standard instruments such as the SF-36. Bruising at the needle placement sites and incident diarrhea were significantly higher in the active acupuncture groups compared to the sham acupuncture groups.

These results show that among Chinese women with PCOS, the use of acupuncture with or without clomiphene does not increase live birth rates. These results show that actual and sham acupuncture, with or without clomiphene, had similar, nonsignificant effects on the rates of live births in Chinese women with PCOS. The authors concluded that these findings do not support acupuncture as an infertility treatment for Chinese women with PCOS.

COMMENTARY

Although it is not uncommon for infertility centers to offer acupuncture to patients, especially those seeking assisted reproduction with in vitro fertilization, evidence of efficacy for increasing live births has not been shown.⁵ This is another study that fails to support acupuncture for improving fertility and live birth outcomes in a specific patient population plagued by ovulatory dysfunction and low fertility. On the other hand, this study bolsters existing evidence supporting clomiphene as first-line pharmacologic therapy for improving live birth rates in infertile women with PCOS.²

PCOS management strategies include diet, exercise, weight loss when needed, and a variety of medications to manage insulin resistance and other symptoms.³ When clomiphene fails in patients with PCOS, strategies to improve fertility also include improving insulin resistance, mainly with metformin.² This practice suggests that insulin resistance may contribute to infertility in these patients, and it begs whether integrative therapies aimed at reducing insulin resistance might be helpful, including acupuncture. Further, the authors suggested that the standardized acupuncture intervention in this study, aimed solely at inducing ovulation, would be atypical of traditional acupuncture treatment, which characteristically is individualized to a specific patient rather than a specific medical condition.

The strengths of this study include its design, methodology, and size. There were similar withdrawal rates across all groups and high adherence rates among participants. Since the study only involved Chinese women in China, the results should not be generalized to women of other ethnic groups or geographic locations. The authors concluded that their findings do not support acupuncture as treatment for infertility due to PCOS. However, without a true control group receiving neither treatment or placebo, one could argue that true and sham acupuncture both improved fertility rates, but less so than clomiphene.

Although acupuncture treatment in this study resulted in increased rates of diarrhea and bruising at needle sites, these side effects, though undesirable, occurred relatively infrequently. Further, the authors cited a clear placebo effect from both actual and sham acupuncture in increasing live birth rates compared to a previous study using physical therapy as a control intervention. Acupuncture is a safe intervention, and few options for treating PCOS-related infertility exist. Despite the absence of evidence of efficacy suggested by this study, there are enough lingering questions to suggest that PCOS patients who wish to pursue individualized acupuncture as an adjunct therapy for infertility should be informed, but not discouraged, assuming cost of treatment is not a burden.

REFERENCES

1. March WA, Moore VM, Willson KJ, et al. The prevalence of polycystic ovary syndrome in a community sample assessed under contrasting diagnostic criteria. Hum Reprod 2010;25:544-551.
2. Homburg R. Polycystic ovary syndrome. Best Pract Res Clin Obstet Gynaecol 2008;22:261-274.
3. Lim CE, Ng RW, Xu K, et al. Acupuncture for polycystic ovarian syndrome. Cochrane Database Syst Rev 2016; May 3: CD007689.
4. Johansson J, Redman L, Veldhuis PP, et al. Acupuncture for ovulation induction in polycystic ovary syndrome: A randomized controlled trial. Am J Physiol Endocrinol Metab 2013;304:E934-E943.
5. Smith CA, de Lacey S, Chapman M, et al. Effect of acupuncture vs sham acupuncture on live births among women undergoing in vitro fertilization — a randomized clinical trial. JAMA 2018;319:1990-1998.