+65 6204 6009 (call) or +65 8809 9396 (sms) hello@somaclinic.sg

Acupuncture and Clomiphene Citrate or Letrozole

Clomiphene Citrate is otherwise known as Clomid or Serophene. Clomiphene is considered the first line of treatment for inducing ovulation in women with PCOS. This oral medication is a weak estrogen-like hormone that acts on the hypothalamus, pituitary gland, and ovary to increase levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH, which is also important in the process of ovulation). The increased level of FSH hormones improves the chances of growing an ovarian follicle that can then trigger ovulation.

Findings from previous clinical and experimental studies indicate that a woman with PCOS who responds poorly to clomiphene and does not ovulate may benefit from acupuncture. Inability of clomiphene to induce ovulation is more likely in patients who are obese, insulin resistant, and hyperandrogenic compared with those who do respond (Imani et al, 1998). Knowing this, there are other studies that suggest the viability of acupuncture treatments to treat obesity, insulin resistance and hyperandrogenism.

Acupuncture is also an alternative in cases where the side effects from Clomiphene kick in. Side effects include hot flushes, breast distension, abdominal distension, nausea/vomiting, nervousness, sleeplessness, headache, mood swings, dizziness, hair loss and disturbed vision. Acupuncture is able to attenuate these side effects. One major side effect of Clomid is that it often causes the uterine lining to thin, which is detrimental to becoming pregnant. Acupuncture causes the uterine lining to thicken and become more uniform by increasing blood flow to the uterine arteries. Stener-Victorin in 1996 did a pilot study measuring the pulsatility index (PI) fo 10 participants undergoinG IVF. After acupuncture, the PI fell, leading to lower blood flow impedance and higher success in IVF. Yu et al in 2006 did a study examining the effect of Viagra and acupuncture on the uterine linings of women who had a history of thin linings (<8mm) in previous IVF cycles. They followed a consistent protocols which improve blood flow to the ovaries and uterus. The researchers found that after acupuncture treatment, the thickness of the lining improved to 10 mm or more in all participating patients.

Last of all, there is research that suggests that prolonged use of clomiphene citrate may be associated with an increased risk of a borderline or invasive ovarian tumour. According to Kousta et al, women responsive to clomiphene citrate should be treated for at least 6 cycles before considering more complex or invasive methods of ovulation induction, and that treatment should probably be limited to a maximum of 12 cycles.

Clomiphene is the current first-line infertility treatment in women with the polycystic ovary syndrome, but aromatase inhibitors, including letrozole, might result in better pregnancy outcomes. Legro et al in 2014 associated letrozole with higher live-birth and ovulation rates (as compared to Clomid) among infertile women with the polycystic ovary syndrome. Howver, in 2005, Dr. Marinko Biljan of Montreal presented an oral abstract at the American Society of Reproductive Medicine (ASRM) annual meeting, reporting congenital anomalies in 150 babies born from infertile women treated with Letrozole. Since then, larger and more comprehensive studies had been done, with adequate data collected to show the efficacy and safety of Letrozole. Letrozole appears to be a good option, with its oral route of administration, cost, shorter half-life and negligible side effects being the main pluses (Sujata Kar 2013). A study done proposed that in PCOS patients resistant to clomiphene and letrozole used as single agents, a combination of the two drugs can be administered before using more aggressive treatment that may have severe complications or surgery. This combination may also be used as a first-line therapy to induce ovulation in severe cases of PCOS in order to save time and expense.

There is one ongoing trial (Li, Ng and Stener-Victorin et al) which is the first randomized controlled trial to compare acupuncture pretreatment followed by letrozole with letrozole alone on live birth in anovulatory infertile women with PCOS. The hypothesis is that acupuncture pretreatment improves insulin sensitivity and leads to a higher ovulation rate and live birth rate, which is different from the available evidence suggesting that acupuncture influences ovulation by affecting the levels of various hormones. We wait the results of this study.

Acupuncture and Second Line Treatments

Acupuncture is worth considering if you are also considering second line treatments. Second line treatments are for when response to Clomiphene is poor.

Metformin (Glucophage) is an oral medication that is mainly used to treat diabetes, it can also be used with PCOS to assist with ovulation, to achieve pregnancy. Velazquez and colleagues reported in an observational study that Metformin made a significant improvement in menstrual regularity and reduction in circulating androgen levels for PCOS women. For some who do not ovulate when treated with Clomid or Metformin alone, could ovulate and have success when both are used together.

When Legros again did a study to compare Metformin and Clomiphene, he concluded that Clomiphene is superior to Metformin in achieving live birth in infertile women with the polycystic ovary syndrome, although multiple birth is a complication. With the exception of pregnancy complications, adverse-event rates were similar in all groups, though gastrointestinal side effects were more frequent, and vasomotor and ovulatory symptoms less frequent, in the Metformin group than in the Clomiphene group.

Zain and colleagues concluded that the ovulation rate was 23.7% in the Metformin group, 59% in the CC group, and 68.4% in the combination treatment group. This was translated into a similar pregnancy rate and live birth, which were higher in the CC and combination groups compared to the Metformin group. Hence, we can deduce that Clomiphene should still be the first-line treatment for ovulation induction in patients with PCOS and the combined drugs used only in severe cases of anovulation. That said, a meta-analysis by Tang et al (2010) suggests there is no evidence that Metformin improves live birth rates (LBR) whether it is used alone or in combination with Clomiphene, or when compared with Clomiphene.

Like Clomiphene, Metformin does come with side effects. We do see more gastronomical tract disturbances. About one third of women on Metformin experienced digestive upset, including symptoms such as nausea, occasional vomiting and loose, more frequent bowel movements, or diarrhea. Acupuncture is useful intervention for preventing and stopping nausea and vomiting – the key acupoint here is PC6. Large trials and studies (Cheong at al 2013 and Ezzo 2006) had confirmed its efficacy.

In cases of poor responders to Clomiphene, an even stronger approach would be to use gonadotropin injections, which are associated with a higher risk of multiple pregnancies and development of Ovarian Hyper-stimulation Syndrome (OHSS). OHSS is more prevalent in PCOS patients, and is a potentially serious side effect of drugs used during IVF. Mild OHSS results in some ovarian enlargement with slight abdominal pain and swelling and the standard medical treatment is pain relief. Moderate OHSS results in more noticeable pain and swelling with nausea and vomiting. Severe OHSS can result in the leakage of hormones and fluid from both ovaries and this in turn may cause accumulation of fluid both in the abdominal cavity and in the chest.

Ovarian hyperstimulation syndrome (OHSS) is a serious complication to expect during the IVF cycle. Any patient undergoing artificial induction of ovulation is at risk of developing OHSS, although some are more at risk than others. The symptoms usually begin four to five days after the egg collection. While up to 33 percent of women experience the mild forms of OHSS, 3-8 percent has reported severe OHSS. Despite significant advances in assisted reproductive technology over the years, there are currently no effective strategies to eliminate this disorder.

If detected early, acupuncture can help eliminate the symptoms of mild OHSS or relieve the discomfort in the severe cases. According to a study done by Nanjing Medical University in 2016, it concluded that electroacupuncture may provide a simple and effective method for the prevention and treatment of OHSS. The results indicate that electroacupuncture can modulate endocrine hormone secretion and affect the secretion of inflammatory cytokines and vascular endothelial growth factor, and thus prevent the progress of OHSS. In another study conducted in 2014, 53 out of 109 women undergoing IVF/ICSI were assigned to electroacupuncture during the cycle. Compared with the non-EA group, the occurrence of OHSS and the canceling rate of transplant cycles were significantly lower in the EA group.

Acupuncture is usually recommended after egg collection to help recovery from anesthetic, local tissue trauma, and most importantly, the prevention of OHSS. The timing and number of acupuncture treatments will vary between women and their individual conditions to best support their recovery before embryo transfer.

Sources:

  1. Hongying Kuang, Yan Li, Xiaoke Wu, Lihui Hou, Taixiang Wu, Jianping Liu, Ernest Hung Yu Ng, Elisabet Stener-Victorin, Richard S. Legro, Heping Zhang, “Acupuncture and Clomiphene Citrate for Live Birth in PCOS: Study Design of a RCT,” Evid Base Complement Alternat Med. 2013; 2013: 527303.
  2. Kousta E, White DM, Franks S. “Modern use of clomiphene citrate in induction of ovulation.” Hum Reprod Update. 1997 Jul-Aug;3(4):359-65.
  3. Impicciatore GG, Tiboni GM. “Ovulation inducing agents and cancer risk: review of literature.” Curr Drug Saf. 2011 Sep 1;6(4):250-8.
  4. Li Chen, Hai-Xiang Sun, You-Bing Xia, Liu-Cai Sui, Ji Zhou, Xuan Huang, Jing-Wei Zhou, Yi-Dan Shao, Tao Shen, Qin Sun, Yuan-Jiao Liang, Bing Yao, “Electroacupuncture decreases the progression of ovarian hyperstimulation syndrome in a rat model,” Reprod Biomed Online. 2016 May;32(5):538-44.
  5. Chen Jun et al, “Investigation on effect of electroacupuncture intervention on in vitro fertilization and embryo transfer of patients with polycystic ovarian syndrome,” Maternal and Child Health Care of China 2009; 30 pg 28 Maternal and Child Health Care of China.
  6. Hong YL, Tan Y, Yin YY, Zou YJ, Guo YH, Nie XW. “Effect of electro-acupuncture on clinical outcomes and ovarian hyperstimulation syndrome in in vitro fertilization and embryo transplantation.” Reproductive Medical Center, Nanjing Jinling Hospital, Nanjing University School of Medicine, Nanjing 210002, China;
  7. Legro RS et al.”Letrozole versus clomiphene for infertility in the polycystic ovary syndrome.” N Engl J Med. 2014 Jul 10;371(2):119-29. doi: 10.1056/NEJMoa1313517.
  8. Biljan MM, Hemmings R, Brassard N. “The outcome of 150 babies following the treatment with letrozole or letrozole and gonadotropins.” Fertil Steril. 2005;84(Suppl 1):S95.
  9. Sujata Kar.”Current evidence supporting “letrozole” for ovulation induction” J Hum Reprod Sci. 2013 Apr-Jun; 6(2): 93–98.
  10. Hajishafiha M, Dehghan M, Kiarang N, Sadegh-Asadi N, Shayegh SN, Ghasemi-Rad M. “Combined letrozole and clomiphene versus letrozole and clomiphene alone in infertile patients with polycystic ovary syndrome.” Drug Des Devel Ther. 2013 Dec 3;7:1427-31.
  11. Stener-Victorin, et al “Reduction of blood flow impedance in the uterine arteries of infertile women with Electro Acupuncture”, Human Reproduction, Vol 11, no6. pp. 1311-17, 1996.
  12. Yu W et al. “A Pilot Study Evaluating the Combination of Acupuncture with Sildenafil on Endometrial Thickness” Presented at the Pacific Coast Reproductive Society Annual Conference 2007
  13. Velazquez EM, Mendoza S, Hamer T, Sosa F, Glueck CJ “Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy.”Metabolism. 1994 May; 43(5):647-54.
  14. Legro RS, Barnhart HX, Schlaff WD, Carr BR, Diamond MP, Carson SA, Steinkampf MP, Coutifaris C, McGovern PG, Cataldo NA, Gosman GG, Nestler JE, Giudice LC, Leppert PC, Myers ER; “Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome.” Cooperative Multicenter Reproductive Medicine Network. N Engl J Med. 2007 Feb 8;356(6):551-66.
  15. Zain MM, Jamaluddin R, Ibrahim A, Norman RJ. “Comparison of clomiphene citrate, metformin, or the combination of both for first-line ovulation induction, achievement of pregnancy, and live birth in Asian women with polycystic ovary syndrome: a randomized controlled trial.” Fertil Steril. 2009 Feb;91(2):514-21.
  16. Ezzo J, Streitberger K, Schneider A.”Cochrane systematic reviews examine P6 acupuncture-point stimulation for nausea and vomiting.” J Altern Complement Med. 2006 Jun;12(5):489-95.
  17. Cheong KB, Zhang JP, Huang Y, Zhang ZJ “The effectiveness of acupuncture in prevention and treatment of postoperative nausea and vomiting–a systematic review and meta-analysis.” 2013 Dec 13;8(12):e82474.