Diminished Ovarian Reserve,Clomid,and Traditional Chinese Medicine: A Case Study

Introduction

The average female reproductive potential peaks at age 25 and then begins to decline. At first, it declines slowly through age 27, and then more quickly to age 35. After age 35, the decline becomes progressively steeper. ¹ Reproductive endocrinologists determine female reproductive potential by assessing ovarian reserve in two primary ways: (1) blood chemistry value of follicle stimulating hormone (FSH) and (2) its relative ratio to estradiol (E2).^2,3 These values can be combined with antral follicle count (AFC), via transvaginal ultrasonography for a more-definitive assessment. ³ When blood samples are drawn on the third day of the menstrual cycle, FSH levels below 10 mIU/mL with E2 levels up to 75 pg/mL are considered to be normal. ¹

The importance of these hormonal values lies in their ability to manage the female reproductive system through a feedback mechanism. When hormone regulation occurs correctly, every cycle provides a 20%–25% chance of conception in optimal circumstances. ¹ Challenges begin to occur when, for reasons that are not fully understood, the ovaries fail to respond to the FSH signal for follicular development. While this is an expected occurrence as women age, it can also arise in younger women, lower their likelihood of conceiving in each cycle from 20% to 5%, and increase the probability of pregnancy loss.^1,2 As a result, women with DOR often seek reproductive assistance to improve their chances of getting pregnant.

Female infertility is diagnosed in women under age 35 if no conception has occurred after 1 year, and in women 35 and over, when there is no conception after 6 months. ¹ Women generally first seek the care of their gynecologists to assist conception before visiting fertility specialists. A common first-round intervention dispensed by gynecologists is ovulation-induction medication, such as clomid/clomiphene citrate.

Clomid is an ovulation-induction medication taken for 5 consecutive days, usually beginning on day 5 of the menstrual cycle. ⁴ Clomid is a selective estrogen-receptor modulator, and although the mechanism of action is not completely understood, ¹ it works to blocks the E2 receptors in the hypothalamus, triggering a release of gonadotropin-releasing hormone (GnRH), which then signals the anterior pituitary to release FSH. ⁴ This increase in circulating FSH signals the ovaries to cause one or more follicles to mature.

Chinese medicine has been used to treat female infertility in China for more then 2000 years, and recent studies suggest that acupuncture improves assisted reproductive outcomes.^5,6 Chinese medicine does not have a DOR disease classification or category. However, more than 2000 years ago, a classical Chinese medicine text described the reproductive lifecycle in a way that mirrors the modern biomedical model closely. The Huang di Nei Jing (The Yellow Emperor's Canon of Internal of Medicine), ⁷ described a natural shift in female fertility in intervals of 7 years, which correlates closely with what is cited in current biomedical literature.

In Chapter 1 of the Huang di Nei Jing, two key concepts are identified regarding the reproductive lifecycle: (1) identification of the Kidneys as the governor of reproduction and (2) reproductive aging as observed in 7-year intervals. At age 28, fertility reaches its “apex” and begins its shift toward vacuity. This mirrors the biomedical statistical observation quite closely, as it is only 1 year after the subtle decline of ovarian reserve begins. ¹ In Chinese medicine, the Kidney's role in governing reproduction is key to healthy fertility.^8–11 Kidney pathologies were the primary TCM diagnosis patterns among females undergoing in vitro fertilization (IVF). ¹² Any etiologic factors the Kidney has to endure, such as repeated reproductive-medicine interventions, will deplete it and ultimately have a negative impact on reproductive outcomes. ¹¹

According to Chinese medical theory, multiple clomid cycles, can deplete the Kidney, Blood, and Yin, and affect the reproductive lifecycle adversely.^9,13

Chinese medicine treatment strategies vary for patients with infertility. Lyttleton, based on the work of Xia Guicheng, described four distinct treatment protocols to administer in accordance with four distinct phases of the menstrual cycle. ⁹ These differ from the usual biomedical menstrual phases of menses, follicular, and luteal phases. According to Lyttleton, the phases are divided up as follows: (1) menses phase (cycle days or CD 1–4); (2) follicular phase (CD 5–11); (3) ovulation phase (CD 12–17), and (4) luteal phase (CD 18–onset of menses). ⁹ Treatment principles change according to the menses phase. Lewis agrees with this treatment strategy (R. Lewis, private communication, 2012). She also recommends the Stener-Victorin et al. protocol ¹⁴ in the follicular phase for patients who require strong tonification.

The objective of this article is to report the outcome of a single case of TCM treatment for DOR that may have been complicated by many consecutive clomid cycles.

Case History

A nulliparous 34-year-old female presented in December 2006 with infertility caused by DOR. The patient was 5′8″ and 160 lbs. She reached menarche at age 13. She reported having regular 27–28-day cycles, and reported menstrual bleeding for 4 days of her cycle. This was a moderate menstrual flow that began with thin, fresh, red or pale red blood, and that tapered off on day 4 of her cycle. At that time, this blood became watery and pale brown. She denied having clotting, but reported that she had mild-to-moderate cramping that occurred up to 5 days prior to her menses and on the first 2 days of her cycle. She ovulated on CD 13 or 14, as confirmed by an ovulation-predictor kit. She also reported seeing some cervical fluid that appeared to be fertile in nature* and denied having any vaginal dryness or dyspareunia. Premenstrually, she noticed increased irritability, bloating, and breast tenderness occurring no more than 5 days prior to onset of her menses. She reported no history of smoking, and she confirmed that she drank no more than 7 (3–7) alcoholic beverages per week.

This patient's biomedical history revealed no prior ovarian surgeries or family history of premature menopause. In the fall of 2005, the patient underwent three consecutive clomid cycles with intrauterine insemination (IUI) while under the care of a women's health nurse–practitioner (NP). No pregnancy resulted. At the time of her initial consultation, in late 2006, her highest recorded FSH reading was 14.5 mIU/mL, and her AFC count was 8–10 bilaterally. Each month, she took 100 mg of clomid and generally produced 1 primary follicle at ovulation. Her NP would then recommend a day for the IUI. She had no information on her endometrial thickness at the time of insemination. However, she reported that, during an ultrasound examination, her NP mentioned that her ovaries were small. Her fallopian tubes had not been evaluated for blockages nor was her uterus evaluated for abnormalities. A sperm analysis showed that her husband's count and motility were normal after processing. No information was available on any morphology testing.

This patient was soft-spoken, with a serious demeanor and a pale complexion. She became weepy and expressed hopelessness and frustration when discussing her fertility challenges. She stated that she found it very difficult to be around babies.

Other significant items that she reported were: low energy; moderate-to-high stress; heavy sleep with difficulty waking; gas and bloating after meals; sugar cravings; daily bowel movements that were occasionally loose or became urgent and/or crampy with stress; mild-to-moderate anxiety that manifested as chest palpitations, chest tightness and, shortness of breath; thirst; nocturia once nightly; frequent urination; no night sweats except when taking clomid; dull, “achey” headaches every 2 weeks; occasional dizziness; and a neutral core body temperature with cold hands and feet.

Her pulses, overall, were slow and deep. On her left side, the pulse was especially deep, soft, and weak in the guan and chi positions. On her right side, the pulse was soft and weak in the chi position. Her tongue was pale purple, swollen and wet.

Her TCM diagnoses were:

(1) Kidney Yang and Essence (Jing) deficiency, as evidenced by her low energy; frequent urination; nocturia; and weak, deep, soft pulses (according to Lyttleton, poor response to medications, small ovaries, and infertility also indicate this diagnosis ⁹ )

Treatment

At this patient's initial consultation, a break from any reproductive interventions for 3 months was recommended; she agreed to this plan. A second biomedical opinion, including a full reproductive workup for her and her husband was also recommended, based on the failure to conceive after three attempts with clomid. Evaluation for male factors was also suggested to ensure that her partner's sperm morphology was normal. The patient declined to follow these last two recommendations.

Weekly acupuncture treatments and Chinese herbal therapy based on the cycle phases described by Lyttleton ⁹ were recommended. The needles used were 0.20×30 mm, Spring type (DBC, Korea) on body points, and 0.16×15 mm, D-type (Red Seirin, Japan) needles without guide tubes on the ears. Chinese herbal medicine (Kaiser Pharmaceutical Co., Ltd., Taiwan) was administered from January through April 2007. All point functions were determined according to A Manual of Acupuncture ¹⁵ and all herb functions were determined according to Chinese Herbal Medicine: Formulas and Strategies, 2nd ed., ¹⁶ unless otherwise noted. When selecting points for treatment, great emphasis was placed on changes in pulse quality when acupuncture points were palpated. If the pulse improved when the point was palpated, it was selected for that treatment. All points were needled to elicit De Qi^17,18 with a lifting thrusting technique and manipulated with an even rotation technique.

Results

The treatment plan described above was performed for 3 months. Following this, the patient discontinued Chinese medical treatment and elected to resume biomedical treatment with a different gynecologist, who was located closer to her home. The new physician discouraged herbal treatment and was unsure about acupuncture's effectiveness.

On a follow-up phone call with the patient, she reported that her FSH was 8.7 mIU/mL in May 2007 and her AFC was 8–9 on each side. She was prescribed 100 mg of clomid, to be taken during CD 5–9. She was instructed to return for an ultrasound on CD 12. She developed 1 primary follicle that was 18.5 mm. Her endometrium was 8.9 mm and trilaminar. She received a human chorionic growth hormone (hCG) trigger shot and was instructed to return 36 hours later for an IUI. She received the IUI on CD14. No pregnancy resulted. This was repeated two more times. Cycle number 2 resulted in 1 primary follicle on CD 11, which was 17 mm, and her endometrium was 8.6 mm. No pregnancy resulted. Cycle number 3 resulted in no primary follicle and her endometrium was 7.2 mm. Again, no pregnancy resulted. Her FSH at the conclusion of these three clomid cycles was now 16.8 and her E2 was 57.7. Her AFC was now 3–4 bilaterally, or <10 total. She was no longer eligible for IVF with her own eggs, and her potential for conceiving naturally based on these measures was now less than 2%. ¹ A year later, she reported via email, that she then pursued donor egg IVF. She conceived successfully and gave birth to a healthy baby girl.

Discussion

It is theorized TCM treatment for 3 months may improve reproductive outcomes when further biomedical interventions are pursued later.^9,11 This is based on supporting the folliculogenesis cycle. Despite the negative outcome for this patient with clomid, she responded quite well to 3 months of TCM treatment: Her FSH was reduced and her AFC was increased. With the increase in her ovarian reserve, she was well-positioned to transition to biomedical in vitro fertilization (IVF). However, it is likely that the repeated clomid interventions following the acupuncture and herbal treatments put her past the acceptable parameters for IVF.

Despite respectful recommendations, the patient reported that she felt she was not giving clomid and her gynecologist enough of a chance to work. She reported that her new doctor was not concerned with pursuing three more rounds of clomid-based IUIs before referral to IVF. It is not uncommon for patients to continue with a doctor despite poor reproductive outcomes. ²⁴ From a Chinese medical perspective, serial use of clomid may be problematic for a woman's reproductive health. Clomid consumes Yin and stagnates Qi. ⁹ Patients who are Yang Deficient tend to respond best to this medication, while patients who are Yin and/or Blood Deficient, or Qi Stagnant (as in the case of this patient) tend to respond quite poorly or have many side-effects.^9,11 Taking clomid for several consecutive months may deplete the Kidney further, damage the Yin, and engender Empty Fire. This was evident in this case by the increasingly poor follicular development response over time caused by repeated use of clomid and by the increased night sweats observed while this patient was on that medication. Favorable reproductive outcomes in patients with DOR—even with pharmaceuticals and reproductive technology—are substantially lower than other infertility diagnostic groups.^2,25–27

TCM fertility specialists frequently treat patients who have undergone—or will soon undergo—many rounds of clomid. It is important to recommend a second opinion when a patient has already completed three cycles using this medication and when research shows clearly that many clomid interventions are not successful.^25–27 In addition, there is a challenge for acceptance of adjuvant Chinese herbal therapy with clomid, as Chinese herbs may improve clomid interventions. ²⁸

It is possible this patient would not have conceived regardless of the three additional clomid cycles after 3 months of TCM treatment. However, she did improve with respect to two important objective measures: FSH and follicle count. More research is needed to investigate the effect acupuncture and Chinese herbs have on ovarian physiology.

Conclusions

Clomid may not be ideal for patients with DOR.^25–27 In this single case, after three failed clomid cycles, this patient with DOR had reduced FSH improved AFC after adjuvant TCM treatment. However, she was still unable to conceive when she underwent three more cycles with clomid. More research is needed to discern which patient population would benefit best from many serial clomid interventions. In addition, ideal treatments for patients with DOR must be investigated, including integrative treatment with assisted reproductive techniques, acupuncture, and Chinese herbs.