By Stacy Frankovitz Reisner, MPH
Age is a significant factor that can affect a woman’s ability to conceive. As many women are postponing childbearing for later in their reproductive lives, infertility is becoming increasingly prevalent. According to the 2013 National Vital Statistics Reports,1 birth rates for women aged 30-39 years and 45-49 years increased (2% and 15% respectively), whereas birth rates declined 2-10% in women under the age of 30. While reasons for delaying childbearing can be various and specific to every woman, several reasons commonly emerge from statistical analysis.
The delay in childbearing is often attributed to pursuing a higher education and the desire for personal establishment with a career or partner. This deferment can compromise one’s ability to conceive. The cause of this decline in fertility is multifactorial, including decreases in viable number of eggs and variations in hormone levels. Females are born with approximately 1-2 million eggs followed by an abrupt decline at puberty, and then a gradual decline to roughly 25,000 eggs by the age of 37. Hormones also rapidly shift later in child-bearing years, contributing to poor egg quality, decreased ovarian reserve, recurrent miscarriages, and menopause. In fact, by the time a woman reaches 40, her chance of conception declines to under 10%.2,3,4
Women over the age of 35 are considered to be of “advanced maternal age” (AMA), when fertility and fecundity typically begin their rapid decline.5 As a result of the decreased ovarian reserves and hormonal imbalances, it is recommended that women 35 and older who have not been able to successfully conceive after six months of unprotected sex see a specialist.3 Many women of AMA seek treatments to improve their chances of conception and desirable pregnancy outcomes.
In the United States, conventional Western medicine’s assisted reproductive techniques (ARTs) and medications have been most commonly used to diagnose and treat women with AMA infertility. While the use of these techniques has been effective in producing live births, traditional Chinese medicine (TCM) has been used to help balance hormones and can complement Western medicine. Ultimately, a woman’s choice between the two different approaches may be dependent upon available health care coverage, finances, personal beliefs, awareness, and treatment previously sought.6-8
Although there is a substantial amount of literature covering female infertility, this review focuses on one area of AMA infertility that was prominent throughout the literature reviewed: primary ovarian insufficiency (also referred to as poor ovarian reserve, diminished ovarian reserve, or premature ovarian failure). This article reviews the existing evidence on the effects of Eastern and Western medicine on AMA-associated infertility and evaluates the research conducted on select hormone levels (FSH and E2) and pregnancy outcomes when using TCM and Western treatments independently or in tandem.
Etiology of Infertility in AMA
In TCM, it is understood that imbalances in yin and yang, the Five Elements, and Zang-fu organ principles are responsible for the reproductive challenges faced by women of advanced age. Both Western medicine and TCM share the concepts of stagnations of energy (qi) or material (blood). Stress and emotional effects have a tendency to impact qi stagnation. Herbal medicine formulas, acupuncture, and moxibustion are routinely used in TCM to prevent and remove these stagnations. The whole medical systems approach of TCM contrasts with the conventional approach of Western medicine, in which a narrow focus, such as on lifestyle, guides treatment and intervention. 7,9,14,16
Due to the multifaceted series of events involving interactions between the hypothalamus, pituitary gland, adrenal glands, ovaries, and uterus, a varying amount of sex hormones is produced each month. These hormones include, but are not limited to, gonadotropin-releasing hormone (GnRH), follicle-stimulating hormone (FSH), estradiol (E2), luteinizing hormone (LH), and progesterone. The onset of menstrual cycle irregularities caused by imbalances in these hormones, other than by certain medical conditions, often begins to occur as a woman’s reproductive potential declines with AMA.4, 17, 18
The relationship between functioning hormones is very delicate and directly influences ovulation. FSH must stimulate the production of ovarian follicles and E2.12 When E2 peaks, the pituitary gland produces LH, which acts as a catalyst for ovulation.19
The declining hormonal environment affecting fecundity is highly complex. Studies have shown that egg quality and quantity diminishes as a result of increased FSH level secretion.2 This will occur when the ovaries do not respond well to FSH secreted by the pituitary gland during the follicular phase of the menstrual cycle. The production of ovarian follicles and E2 stimulated by the FSH secretion, which supports ovulation and the production of LH, becomes inadequate, resulting in an increase of FSH levels. As a woman ages, this response system continues to generate higher FSH levels as the ovaries lose sensitivity. This rise in FSH secretion is indicative of a decline in the woman’s reproductive potential and the remaining reserve, as it notably reflects what is known as primary ovarian insufficiency. Measuring these hormones is one method commonly used by reproductive endocrinologists to determine treatment efficacy in this population. 11, 13, 18, 20
Although the oocyte (mature egg) degenerative process commences at birth and continues until menopause, it occurs most rapidly in AMA females, but the rate at which it occurs varies from individual to individual. Generally, from the ages of 35 to 50, progesterone and estrogen decrease to 75% and 35%, respectively. The imbalance may be caused by luteal insufficiency, commonly due to perimenopause. Women of AMA experience menstrual changes several years before the termination of menstruation. Once the transition to menopause begins, fewer than 1000 follicles containing eggs remain, making it unlikely for a woman to conceive.4,23-25
Women of AMA often experience a decline in pregnancy rates and an increase in miscarriage rates. While there are multiple causes of recurrent pregnancy loss, the rate of miscarriage appears to be higher in women with POI. In fact, the risk of fetal loss is two-to-three-fold higher in women of AMA due to chromosomal abnormalities or due to a deficiency in progesterone levels. AMA females aged 40-42 have a 25% chance of miscarriage that steadily rises to 50% or more by 43-46 years of age.10,13,22,24
Tests and diagnosis for infertility attributed to Advanced Maternal Age
Women of AMA who experience POI are typically diagnosed with yin deficiency with heat, but, excessive yang, spleen qi deficiency, kidney yin and yang deficiency, and blood deficiency have also been attributing patterns to POI. Signs and symptoms, often similar to the Western diagnosis of menopause, can include night sweats, increased dryness, inadequate estrogen production, fluctuating FSH levels, and absent or markedly irregular menses. Other vacuity patterns can be seen as a red with thin yellow or no coat on the tongue and a fine and rapid pulse.10,12,25
In contrast, the evidence-based approach to infertility in Western medicine focuses on the physical condition and disease. The self-administered diagnostic test of basal body temperature (BBT) readings is sometimes used to monitor a woman’s temperature throughout her cycle. This method examines whether or not ovulation has occurred as well as possible defects to the menstrual cycle. Readings from this method may foster a greater understanding of temperature levels as they relate to hormones such as FSH and progesterone. A decrease in progesterone, for example, may be marked by lower temperature readings in the second half of a woman’s menstrual cycle, suggesting a luteal phase defect or possibly a threatened miscarriage.7,17,26
Other diagnostic measures include blood tests to measure hormone levels and over-the-counter ovulation predictor kits (OPKs) to anticipate ovulation. The analyses of basal FSH and estradiol levels in the blood have been historically used to predict an AMA woman’s ovarian reserve. FSH levels greater than 10 IU/L, when measured on day 3 of the menstrual cycle, can signify poor ovarian response. Likewise, estradiol levels greater than 60-80 pg/mL also suggest POI. Measurements of both FSH and E2 on day 3 of the menstrual cycle, rather than independently, are most useful in determining POI. Alternatively, OPK urine tests measure LH and E2 hormones to predict ovulation. 24 to 36 hours preceding the release of an egg, LH levels dramatically surge. In women with POI, however, this diagnostic test may not be as reliable due to consistently elevated LH levels and low levels of E2.4,13,27
Similarly, the clomiphene citrate challenge test (CCCT) and gonadotropin-releasing hormone agonist stimulation test (GAST) measure FSH levels to assess ovarian reserve and perimenopause status in women 35 years or older. There is also evidence that the anti-Mullerian hormone (AMH) is a reliable marker for ovarian function, since it is more stable and predicts ovarian response to ART as well. Testing serum progesterone levels can support the identification of a luteal phase defect responsible for recurrent pregnancy loss in women of AMA. Ultrasounds are another test to determine antral follicle count for ovarian reserve and fetal viability.4,7,17,28
TCM provides a variety of treatment options such as Chinese herbal therapy, acupuncture, acupressure, moxibustion, dietary and lifestyle recommendations, and massage for balancing yin and yang.7, 8 Current literature in Eastern medicine examines the effects of the most widely used treatments of acupuncture and Chinese herbal medicine. Several studies have reported positive results using these techniques.29-34
As a major element of TCM, acupuncture promotes the flow of qi and blood within the channels to restore energy and hormone balance within the body.30 Acupuncture has been found to decrease FSH and LH levels and increase E2 levels, which might be evidence of possible mechanisms behind the effectiveness of acupuncture in modulating the menstrual cycle. In a small prospective observational study, Zhou et al. (2013) found that there was a difference of 39.8 IU/L overall decrease in serum FSH levels, a 14.81 IU/L decrease in serum LH, and an 184.18 pmol/L increase in serum E2 levels compared to baseline levels in all 11 patients treated with electro-acupuncture. The effects of this treatment were observed throughout the three-month follow-up period.
In addition to modulating certain hormone levels, more recent studies found improvements in menstruation or its symptoms.33, 34 Chen et al. (2014) highlighted that 19.4% of the 31 women evaluated in their prospective case series pilot study saw improvement in their menses after three months of treatment. Similar effects on the reduction of FSH and LH and an increase in E2 levels were noted in these women. Wang et al.’s (2014) results from their prospective cohort study found that menstruation was recovered in 16.7% of the 30 cases assessed and saw an improvement in perimenopausal symptoms in POI women at 6 months in this study. However, contrary to Zhou et al. (2013) and Chen et al.’s (2014) studies, there was no statistical difference in FSH levels before and after treatment.
Chinese herbal medicine (CHM) is another widely used treatment of TCM. CHM has been found to promote restoration of hormones and improve pregnancy outcomes with minimal to no side effects.29 There are more than 100 different herbs that can be formulated for an individual’s specific symptoms. The premise of Chinese herbs is to help the body regulate correct levels of hormones on its own.6 In Wing & Sedlmeier’s (2006) prospective cohort clinical study, the authors saw the same significant reduction in FSH levels between pre- and post-treatment assessments in both younger and older women at 6 months, suggesting that CHM is just as effective for women of AMA. Additionally, after six months of treatment, there was an overall 56% pregnancy outcome in this study.
A subsequent systemic review by Reid & Stuart (2011) confirmed CHM’s efficacy by observing a 3.5 times increase in pregnancy outcomes with CHM compared to Western medicine’s drugs alone in 1851 women with infertility over a four-month period. In a more recent clinical observation study, Huang et al. (2014) noted that after three consecutive months of taking a particular combination of CHM, 40 POI patients saw an effective therapeutic rate of 92.5%, compared to 73.68% of the 38 cases of POI patients taking hormone replacement therapy (HRT).
The available literature on acupuncture and CHM shows promising results for women of AMA with POI. Since there is a decline in egg quality and quantity in these women, the data suggests that acupuncture and CHM may enhance a woman’s reproductive environment by improving hormone imbalances and increasing pregnancy outcomes. While these two methods are commonly practiced in tandem, the independent results from these approaches indicate that women of AMA may improve their treatment results with either option.
There are several different treatment modalities available within Western medicine for female infertility. For women with POI, treatments options include hormone injections, hormone replacement therapy, dehydroepiandrosterone (DHEA) supplementation, cryopreservation of oocytes and/or ovarian tissue, donor oocytes and assisted reproduction technologies (ART), primarily via IVF. Of these, the literature in Western medicine suggests that IVF with donor oocytes may be the most promising means of overcoming age-related infertility.4,35
The success rate with the use of donor oocytes during IVF is reported to be as high as 48.4%, with an increase in success rate in patients undergoing successive cycles. In one 2007 retrospective study involving 8,430 donor oocyte cycles, patients undergoing 3 cycles had success rates of 87% while those undergoing 5 cycles had success rates as high at 96.8%.36 The proposed explanation for the increased rate of success with the use of donor oocytes versus autologous oocytes is age-related oocyte deterioration. This was demonstrated in a prospective observational study of 86 AMA females with decreased FSH and peak E2 levels, in which poor IVF responders in AMA and non-AMA groups achieved different success levels despite similar treatment regimens after 11 days of ovarian stimulation. The study ultimately demonstrated that poor response to hormones and age-related deterioration of the oocytes contributes to the challenges that women with POI face with traditional IVF treatment.37
Similarly, this study also supports the evidence that higher success rates were achieved when using donor oocytes during IVF in AMA females. While higher success rates have been seen with donor oocytes, there are inconsistent findings that suggest using donor oocytes in women of AMA may increase the risk of pregnancy complications. Pregnancy-induced hypertension was seen in as many as 26% of women compared to the 8% seen in the standard IVF group. Despite such complications, the use of donor oocytes over autologous oocytes is still preferred.38,39
The success rate of fertilization in women of advanced maternal age using autologous oocytes and undergoing IVF alone is considerably low. Multiple studies have shown a decreased number of clinical pregnancies each year after the age of 40 along with a simultaneous rise in spontaneous miscarriage after IVF treatment. Several studies have reported low rates of conception, with women age 41 – 43 having pregnancy rates between 5 and 15% and successful delivery rates of a healthy infant between 2 and 7%. In these studies, the data revealed that women over 45 years old had 0% success rate with IVF alone. Despite the low success rates, many AMA females wish to use autologous eggs to become pregnant. To address the low success rate of IVF in women of AMA who wish to use autologous oocytes, hormone supplementation and modification was added to the treatment protocols.21,35,40,41
Pretreatment with HRT and DHEA are often used to enhance increased ovulation as well as possibly help restore hormone balance. In a double-blinded study of 50 women aged 24-39 with POI, subjects were pretreated with ethinyl-E2. Of the previously anovulatory women, 32.4% achieved successful ovulation after 2 weeks of ovarian stimulation.42 DHEA has also been demonstrated to increase pregnancy rates when used as a pretreatment method and during IVF treatment, with birth rates reaching 21% versus 4% in controls in a study involving 33 POI women with a mean age of 36.9 years.43
Additional studies have shown an increase in pregnancy rates and restoration of sex hormones to relatively normal levels after supplementation with DHEA. Barad & Gleicher’s (2006) case-control study found that DHEA yielded increased fertilization rates and embryo quality. A further retrospective cross-sectional and longitudinal analysis study by Gleicher et al. (2010) in 120 patients demonstrated a 23.64% pregnancy rate and 60% mean improvement in AMH concentration after 90-120 days on DHEA. Similarly, in an observational study conducted by ASRM (2009), results showed a reduction of FSH levels while simultaneously increasing E2 levels post-treatment of DHEA, supporting DHEA’s role in helping to achieve optimal hormone levels necessary for conception.44-46
Other treatment options available to women of AMA with POI that wish to use autologous oocytes are cryopreservation and transplantation, and ovarian stem cells. Cryopreservation is a process where tissue or eggs are preserved by freezing them in temperatures below zero degrees. The first live birth from using transplanted cryopreserved ovarian tissue was seen in a 31-year-old female patient previously treated for Hodgkin’s disease. Subsequent studies have also reported an increased number of live births using this approach. In a recent 2-year prospective study, 37 patients with POI underwent ovariectomy using a new technique for tissue cryopreservation with subsequent re-transplantation of ovarian tissue strips, which resulted in follicle growth in 45% of the patients and two live pregnancies.47-49
While ovarian tissue cryopreservation is a possible alternative for women of AMA, it appears more effective in women under 40 in the earlier stages of POI. Alternatively, cryopreserving oocytes has become increasingly popular. In a prospective randomized study involving 230 subjects during a 4 year period, newer techniques in cryopreservation have reported pregnancy rates as high as 38% compared to 13% using regular methods of cryopreservation due to less damage to the DNA during the thawing process.50
The use of stem cells is also being explored in female infertility. Their ability to differentiate into different cell types offers great promise, as these cells could differentiate into genetically identical gametes of the AMA woman’s oocyte. Innovative approaches involving the use of ovarian stem cells (OSCs) may offer a possible strategy for enhancing a woman’s ability to conceive. Evidence in a mouse model demonstrated that transplanted ovarian germline stem cells can form functional oocytes. This result supports the findings in Bukovsky et al.’s (2006) and Marques-Mari et al.’s (2009) earlier reviews stating that the differentiation of germ cells from stem cells could eventually be a possible method of producing autologous oocytes for women of AMA.51-53
Many of the treatment options for women of AMA experiencing POI show some success in achieving a live birth; however, the outcome is still very low. The literature on women wishing to pursue IVF with autologous oocytes shows that this method is not the most effective treatment modality for improving conception rates. HRT and DHEA supplementation offer only slightly higher pregnancy rates than other methods of treatment. Cryopreservation and transplantation techniques may not improve the age-related decline in egg quality in older women, so this experimental approach is most suitable when sought earlier in the reproductive years.49 Similarly, ovarian stem cells may offer alternative solutions in the future, but the data to support this approach are extremely limited. Ultimately, IVF with donor eggs demonstrates the most optimal outcome; for women of AMA who want to use autologous eggs, however, the treatments above are viable options.
Although IVF is the most commonly used technology for fertility assistance, the average IVF live birth rate is only 5-15% with autologous oocytes. Today, many women of AMA undergoing IVF are seeking TCM as an adjunct therapy to improve their pregnancy outcomes. Several studies have described beneficial results when implementing Eastern medicine in conjunction with Western medicine. A landmark study conducted by Paulus et al. (2002) compared the pregnancy rates of two groups of women 21-43 years old undergoing IVF. In their prospective randomized study involving 160 patients, they found that, 14 to 16 days after embryo transfer, the group receiving acupuncture had a 42.5% pregnancy rate compared to a 26.3% pregnancy rate in the non-acupuncture control group. Haeberle et al.’s (2006) abstract substantiated the results of Paulus et al.’s (2002) study and further observed a statistically significant improvement in IVF fertilization rates in women over the age of 35. Improved pregnancy outcomes with combined acupuncture and IVF therapy were also demonstrated in a prospective randomized trial including 273 women with an average age of 37 years.9,21,40,41,54,55-57
Of the three randomized groups studied (control group who received no acupuncture, ACU 1 who received acupuncture on day of Egg Transfer [ET], and ACU 2 who had acupuncture on the ET day and again two days later), clinical and ongoing pregnancies were significantly higher in the acupuncture group (ACU 1) (39%, 26%, and 36%) as compared to the control group (22%). While clinical and ongoing pregnancies were higher in ACU 2 as compared to the control, statistical significance was not demonstrated. These studies showed that acupuncture used during IVF egg retrieval and embryo transfer resulted in higher pregnancy results.55-57
In contrast to the earlier findings comparing acupuncture alone with IVF, recent studies demonstrated no statistical differences in pregnancy outcomes by age group when women of AMA undergoing IVF were included. These studies included comparisons between a “sham” group and an acupuncture group. The sham design was used to control for placebo effects. Moy et al.’s (2011) randomized control study observed a 45.3% clinical pregnancy rate in the acupuncture group and 52.7% for the sham group in 160 infertile women ages 18-38. Results were assessed 14 days after retrieval followed by 2 days post the first positive serum beta-hCG reading.58-60
A more recent and smaller 60 patient randomized controlled, multi-center, sham-treated trial by Udoff et al. (2014) published that the pregnancy rate in the acupuncture group was 57.1% versus 52.4% in the control groups. However, the authors noted a slightly higher delivery rate for the acupuncture group (54.5%) compared to the sham group (42.9%).
While there is limited literature on the effects of acupuncture in combination with CHM as an adjuvant treatment to IVF, a few investigations support the benefits of this combination therapy in women of AMA. In a single case study involving a 41-year-old female with POI, Rubin (2010) demonstrated that the combined effects of CHM and acupuncture during IVF had safely produced a viable baby girl. While pregnancy was achieved in a 41-year-old female, Daghighi (2011) saw a decrease in FSH and an increase in E2 levels in addition to symptoms reductions in a 39-year-old female case study using the integrative treatment. In a four-month timeframe, FSH levels dropped 15 values and E2 values increased 19.94, which put the female within the normal range.
In a recent retrospective cohort study, 1231 IVF patient records were evaluated for effects of CHM and acupuncture on IVF.54 This study compared three groups of women with a mean age of 35 years old experiencing diminished ovarian reserve or other infertility challenges: usual care, whole systems TCM, and acupuncture. Women were also differentiated by donor and non-donor cycle types. Of these groups, 85.7% of women treated with both CHM and acupuncture had live births compared to 62.5% in usual care and 59.5% in acupuncture alone.
Treatment alternatives for women of AMA using an integrative approach are becoming increasingly common. The literature on acupuncture accompanying IVF has demonstrated inconsistent results as an effective adjuvant treatment for women of AMA. The inconsistencies may be primarily attributed to possible placebo effects, nonstandard acupuncture points, and acupuncture performed by multiple practitioners. Additionally, while the “sham” is believed to control for the placebo effect, there are concerns that sham has some active properties.60 This may also suggest that the sham points were a weaker form of acupuncture, therefore proving that real acupuncture is truly effective. However, while there is limited available data combining CHM and acupuncture in IVF, this approach appears to have the most beneficial results in women of AMA.
A review of the literature on the effects of Eastern and Western medicine in AMA infertile women with POI illustrated that as sole therapies as well as in conjunction, Eastern and Western medicine may be effective in supporting yin and yang/hormone balance and pregnancy results. While the studies using acupuncture and CHM had shown beneficial effects on hormone and pregnancy outcomes, many of them were seriously limited by their sample sizes and sources of bias, including non-random misclassification of exposure (NME) from the lack of blinding in treatment methods. In addition, several of the study designs lacked controls, standardized treatments, and randomization; they were also prone to possible confounding and limited generalizability due to a lack of a representative population. Despite these limitations, many of the studies were able to confirm previous findings from other authors which strengthened the argument that TCM may improve reproductive outcomes. While some of the sample sizes may not have been statistically significant, these studies still offer valuable information to practitioners seeking to understand the potential efficacy of these approaches.
Similarly, some of the studies for Western medicine had notable limitations. The observational studies cited may have been subject to selection bias, confounding, and difficulty in establishing temporality between the female’s hormone levels/pregnancy outcomes and the treatment provided. These biases may have threatened the overall internal validity to the research conducted. Similar to the studies conducted on Eastern medicine treatments, many studies on Western medicine treatments also evaluated only a homogenous population, which limited generalizability.
Additionally some of these studies, such as donor oocytes, tissue/embryo cryopreservation, and ovarian stem cells, are considered experimental and controversial due to the ethical considerations they impose on society. In spite of these validity concerns, there were sufficient well-designed randomized control trials that demonstrated beneficial effects of some techniques that women of AMA could use as possible treatment options.
Ideally, a larger heterogeneous population evaluated in a randomized control setting is needed to minimize selection bias, NME, and confounding as well as to enhance generalizability for both Eastern and Western studies. Furthermore, more research is needed within Eastern medicine to understand the mechanism of action and application of acupuncture and CHM without compromising individual treatment methods. In some cases, the use of more in vivo studies in Western medicine would make the technique more translatable to the effects that it would have on the human system. Introducing more studies that specifically evaluate women of AMA with POI are needed for both Eastern and Western medicine. Additionally, recognizing the inherent differences between the two medical cultures may facilitate a wider understanding and broadened treatment options for these women.
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Stacy Frankovitz Reisner received a Master’s of Public Health from the University of Massachusetts Amherst. Her interest in integrative medicine and age-related infertility led her to explore this topic in depth. Stacy has over 15 years of experience in biotechnology and currently resides in San Francisco, California.