**5. Traditional Chinese medicine**

Traditional Chinese medicine (TCM) formulas have been used to treat female and male infer‐ tility for hundreds of years. Classically, the TCM formulas are combined with several single herbs to treat a specific disease. Some of the single herbs that have been used in women include Semen Cuscutae, Semen Lantaginis, Herba Leonuri Japonici, and Fructus Ligustri Lucidi, and were first recorded in the Chinese classic Shi Jing (the Book of Songs) over 2000 years ago.

#### **5.1. Female infertility**

The results of one systematic review revealed that treatment with Chinese herbal medicine can increase pregnancy rates 2‐fold in a 4‐month period compared to western fertility drugs or IVF [41]. This report also stated that evaluating the quality of the menstrual cycle is essen‐ tial in order to effectively treat female infertility by TCM. However, in a recent well‐con‐ trolled clinical trial, there was no significant difference in fertility outcomes after laparoscopy between women with minimal/mild endometriosis treated with oral contraceptives (OC), or OC and Dan&e mixture (composed of six herbs) [42]. A study from the National Health Insurance Research Database (NHIRD) in Taiwan has revealed the most commonly used TCM formulas for the management of female infertility [43]. At the top of the list are Dang‐Gui‐Sha‐ Yao‐San and Wen‐Jing‐Tang; the former is used for abdominal pain during pregnancy, while the latter is used for dysmenorrhea and infertility, and acts by promoting blood circulation to prevent blood stasis, by warming the meridians to dissipate cold, and by tonifying qi to nourish the blood. The herbal formulas and single herbs commonly used for the treatment of female infertility are described below. The effects of these herbs on the endocrine regulation effects of the menstrual cycle and the ovulation rate will also be explored. Other commonly prescribed formulas that are used to relieve infertility‐related symptoms and diseases such as premenstrual syndrome (Jia‐Wei‐Xiao‐Yao‐San), irregular menstrual cycles (Zou‐Gui‐Wan, You‐Gui‐Wan), uterine fibroids (Gui‐Zhi‐Fu‐Ling‐Wan), diarrhea during menstruation (Shen‐ Ling‐Bai‐Zhu‐San), dysmenorrhea (Shao‐Fu‐Zhu‐Yu‐Tang), abnormal uterine bleeding (Gui‐ Pi‐Tang), amenorrhea, or oligomenorrhea (Si‐Wu‐Tang), do not fall within the scope of this review.

#### **5.2. Male infertility**

**4. Conventional treatments and limitations**

92 Chinese Medical Therapies for Diabetes, Infertility, Silicosis and the Theoretical Basis

for up to 4% of infants born in developing countries.

especially IVF‐ET and ICSI, are costly and risky [38].

both with and without OH [39].

**5.1. Female infertility**

**5. Traditional Chinese medicine**

Assisted reproductive technology (ART), such as artificial insemination (AI), *in vitro* fertiliza‐ tion and embryo transfer (IVF‐ET), and intracytoplasmic sperm injection (ICSI), is responsible

ART has several iatrogenic complications including the risk of multiples, low luteal phase insufficiency, disabled embryo implantation, ovarian hyperstimulation syndrome (OHSS), and other perinatal and long‐term health conditions [37]. Furthermore, fertility treatments,

Intra‐uterine insemination (IUI), one form of AI, is a commonly used fertility treatment for couples with cervical factor infertility, unexplained subfertility, and subfertility in women with endometriosis after surgical resection [39]. IUI is more useful in some types of severe sex‐ ual dysfunction such a severe ejaculatory dysfunction or vaginismus; in cases of cervical factor or mild male factor infertility; and to prevent the transmission of sexually transmitted diseases such as hepatitis B/C virus (HBV/HCV) and human immunodeficiency virus (HIV) [40].

It is a relatively simple surgical procedure whereby semen that has been washed in the labo‐ ratory is inserted into the uterine cavity by using a small catheter at the time of ovulation. IUI allows sperm to bypass the potentially hostile cervix, and thus increases the number of sperm that reach the uterine cavity and oocyte [40]. The technique can be performed either with or without added medications to encourage ovarian hyperstimulation (OH). In the latter method, follicular growth is monitored either via regular ultrasound monitoring to visualize the follicles or by measuring the preovulatory luteinizing hormone level rise in the serum or urine. In the former, ovulation is induced by an injection of human chorionic gonadotropin (hCG). Timed intercourse (TI), a less invasive method than IUI, involves giving couples infor‐

Nevertheless, a systematic review revealed that there is no difference in live birth or multiple pregnancy rates in most couples with unexplained subfertility treated with either IUI or TI,

Traditional Chinese medicine (TCM) formulas have been used to treat female and male infer‐ tility for hundreds of years. Classically, the TCM formulas are combined with several single herbs to treat a specific disease. Some of the single herbs that have been used in women include Semen Cuscutae, Semen Lantaginis, Herba Leonuri Japonici, and Fructus Ligustri Lucidi, and were first recorded in the Chinese classic Shi Jing (the Book of Songs) over 2000 years ago.

The results of one systematic review revealed that treatment with Chinese herbal medicine can increase pregnancy rates 2‐fold in a 4‐month period compared to western fertility drugs

mation about cycle monitoring so that they can time intercourse appropriately.

A recent study revealed that changes in the metabolic pathways, which regulate aromatic amino acids, tricarboxylic acid cycle, and sphingolipid metabolism may play an important role in the origin of Kidney‐Yang deficiency syndrome (KYDS)‐associated male infertility [44]. This research offered a new way for metabolomics analysis of seminal plasma to differentiate TCM syndromes of infertile males. The Chinese medicine Huzhangdanshenyin is used for male immune‐factor infertility and has been shown to be more effective than prednisone [45]. The medicine works by improving the antisperm‐antibody‐reversing ratio; and ameliorating sperm indexes such as sperm motility, viability, and density, without severe adverse effects. Another Chinese medicine, Bushen Shengjing Decoction (BSSJD), has the effect of decreasing semen levels of reactive oxygen species (ROS), improving the quality of sperm, and increasing the natural fecundity of patients with severe oligospermia and azoospermia (SOA), thus rais‐ ing the viability of their sperm in order to increase the ovarian fertilization rate and clinical pregnancy rate in ICSI cycles [46].

#### **5.3. Chinese herbal formulas for infertility**

#### *5.3.1. Dang‐Gui‐Sha‐Yao‐San*

Dang‐Gui‐Sha‐Yao‐San consists of Angelicae sinensis Radix, Paeoniae Radix, Poriz, Atractylodis ovatae Rhizoma, Alismatis Rhizoma, and Ligustici Rhizoma. According to the principles of TCM, Dang‐Gui‐Shao‐Yao‐San has the effect of nourishing liver blood, invig‐ orating the spleen, and eliminating wetness. A previous study which used a Grading of Recommendations Assessment, Development and Evaluation method (GRADE) to evaluate the quality of evidence for Dang‐Gui‐Sha‐Yao‐San concluded that this formula was likely to be beneficial and safe for the treatment of primary dysmenorrhea [47]. Another clinical study showed that it may be useful for resolving the symptoms of mild or moderate hypochromic anemia secondary to uterine myoma‐induced menorrhagia [48].

#### *5.3.2. Wen‐Jing‐Tang*

Wen‐Jing‐Tang consists of Cinnamomi Ramulus, Evodiae Fructus, Ligustici Rhizoma, Angelicae sinensis Radix, Paeoniae Radix, Zingiberis Rhizoma Recens, Moutan Radicis Cortex, Ophiopogonis Tuber, Pinelliae Tuber, Ginseng Radix, Glycyrrhizae Radix, and Asini Corii Gelatinum. According to the principles of TCM, Wen‐Jing‐Tang has the effect of pro‐ moting blood circulation to dispel blood stasis, of dispelling cold by warming the meridians, of benefiting qi, and of nourishing the blood. Wen‐Jing‐Tang has been shown to effectively regulate endocrine conditions such as plasma LH and estradiol levels in PCOS patients with ovulatory dysfunction without taking eight‐principle pattern identification into consider‐ ation. The study concluded that Wen‐Jing‐Tang can be used to treat PCOS in women with various constitutions (as determined by the matching theory of eight‐principle pattern iden‐ tification) in clinical management [49]. Another report showed that combined therapy with Wen‐Jing‐Tang and clomiphene induced ovulation without OHSS in infertile patients who did not respond to clomiphene citrate alone [50].

#### *5.3.3. Jia‐Wei‐Xiao‐Yao‐San*

Jia‐Wei‐Xiao‐Yao‐San consists of Moutan Radicis Cortex, Radix Paeoniae Rubra, Bupleuri Radix, Angelicae Sinensis Radix, Atractylodis Ovatae Rhizoma, Poria, Glycyrrhizae Radix, Zingiberis Rhizoma Recens, and Menthae Herba. According to the principles of TCM, Jia‐ Wei‐Xiao‐Yao‐San disperses stagnated liver qi, suppresses heat, and nourishes the blood. According to the NHIRD in Taiwan, Jia‐Wei‐Xiao‐Yao‐San‐based Chinese herbal medicine combinations were most frequently used for PMS and primary dysmenorrhea [51]. However, the exact mechanism whereby Jia‐Wei‐Xiao‐Yao‐San improves fertility is unclear. In one study, Jia‐Wei‐Xiao‐Yao‐San had no effect on serum levels of E2 and FSH, but did improve climacteric symptoms, especially in patients with hormone replacement therapy resistance who strongly complained of psychological symptoms [52]. These findings imply that Jia‐Wei‐ Xiao‐Yao‐San may affect fertility via as‐yet undiscovered mechanisms.

#### *5.3.4. You‐Gui‐Wan*

You‐Gui‐Wan consists of Rhizoma Rehmanniae Praeparata, Rhizoma Dioscoreae, Fructus Lycii, Fructus Corni, Eucommia ulmoides Oliv, Semen Cuscutae, Colla Cornus Cervi, Angelicae sinensis Radix, Radix Aconiti Praeparata, and Cinnamomum cassia Blume. According to the principles of TCM, You‐Gui‐Wan acts by gently reinforcing the Kidney‐Yang, supplement‐ ing body essence, and replenishing blood. Previous research has shown that You‐Gui‐Wan medicated serum can significantly increase the percentage of mature oocytes, and modulate mRNA expression of a number of signaling molecules including protein kinase A (PKA), cAMP‐response element binding protein (CREB), mitogen‐activated protein kinases (MAPK), protein kinase C (PKC), protein kinase G (PKG), maturation promoting factor (MPF), as well as concentrations of cyclic adenosine monophosphate (cAMP), cyclic guanosine monophos‐ phate (cGMP), and nitric oxide (NO) [53]. It has also been reported that patients treated with You‐Gui‐Wan had higher rates of successful IVF compared to those treated with FSH (with or without normal serum). In animal studies, You‐Gui‐Wan has been shown to increase sperm fertilizing ability by increasing sperm acrosin activity and promoting the acrosome reaction, which resulted in a higher percentage of zygotes in mice treated with You‐Gui‐Wan com‐ pared to control mice [54].

#### *5.3.5. Zou‐Gui‐Wan*

the quality of evidence for Dang‐Gui‐Sha‐Yao‐San concluded that this formula was likely to be beneficial and safe for the treatment of primary dysmenorrhea [47]. Another clinical study showed that it may be useful for resolving the symptoms of mild or moderate hypochromic

Wen‐Jing‐Tang consists of Cinnamomi Ramulus, Evodiae Fructus, Ligustici Rhizoma, Angelicae sinensis Radix, Paeoniae Radix, Zingiberis Rhizoma Recens, Moutan Radicis Cortex, Ophiopogonis Tuber, Pinelliae Tuber, Ginseng Radix, Glycyrrhizae Radix, and Asini Corii Gelatinum. According to the principles of TCM, Wen‐Jing‐Tang has the effect of pro‐ moting blood circulation to dispel blood stasis, of dispelling cold by warming the meridians, of benefiting qi, and of nourishing the blood. Wen‐Jing‐Tang has been shown to effectively regulate endocrine conditions such as plasma LH and estradiol levels in PCOS patients with ovulatory dysfunction without taking eight‐principle pattern identification into consider‐ ation. The study concluded that Wen‐Jing‐Tang can be used to treat PCOS in women with various constitutions (as determined by the matching theory of eight‐principle pattern iden‐ tification) in clinical management [49]. Another report showed that combined therapy with Wen‐Jing‐Tang and clomiphene induced ovulation without OHSS in infertile patients who

Jia‐Wei‐Xiao‐Yao‐San consists of Moutan Radicis Cortex, Radix Paeoniae Rubra, Bupleuri Radix, Angelicae Sinensis Radix, Atractylodis Ovatae Rhizoma, Poria, Glycyrrhizae Radix, Zingiberis Rhizoma Recens, and Menthae Herba. According to the principles of TCM, Jia‐ Wei‐Xiao‐Yao‐San disperses stagnated liver qi, suppresses heat, and nourishes the blood. According to the NHIRD in Taiwan, Jia‐Wei‐Xiao‐Yao‐San‐based Chinese herbal medicine combinations were most frequently used for PMS and primary dysmenorrhea [51]. However, the exact mechanism whereby Jia‐Wei‐Xiao‐Yao‐San improves fertility is unclear. In one study, Jia‐Wei‐Xiao‐Yao‐San had no effect on serum levels of E2 and FSH, but did improve climacteric symptoms, especially in patients with hormone replacement therapy resistance who strongly complained of psychological symptoms [52]. These findings imply that Jia‐Wei‐

You‐Gui‐Wan consists of Rhizoma Rehmanniae Praeparata, Rhizoma Dioscoreae, Fructus Lycii, Fructus Corni, Eucommia ulmoides Oliv, Semen Cuscutae, Colla Cornus Cervi, Angelicae sinensis Radix, Radix Aconiti Praeparata, and Cinnamomum cassia Blume. According to the principles of TCM, You‐Gui‐Wan acts by gently reinforcing the Kidney‐Yang, supplement‐ ing body essence, and replenishing blood. Previous research has shown that You‐Gui‐Wan medicated serum can significantly increase the percentage of mature oocytes, and modulate mRNA expression of a number of signaling molecules including protein kinase A (PKA), cAMP‐response element binding protein (CREB), mitogen‐activated protein kinases (MAPK), protein kinase C (PKC), protein kinase G (PKG), maturation promoting factor (MPF), as well

Xiao‐Yao‐San may affect fertility via as‐yet undiscovered mechanisms.

anemia secondary to uterine myoma‐induced menorrhagia [48].

94 Chinese Medical Therapies for Diabetes, Infertility, Silicosis and the Theoretical Basis

did not respond to clomiphene citrate alone [50].

*5.3.2. Wen‐Jing‐Tang*

*5.3.3. Jia‐Wei‐Xiao‐Yao‐San*

*5.3.4. You‐Gui‐Wan*

Zou‐Gui‐Wan consists of Colla Cornus Cervi, Colla Plastri Testudinis, Rhizoma Rehmanniae Praeparata, Rhizoma Dioscoreae, Fructus Lycii, Fructus Corni, Radix Cyathulae, and Semen Cuscutae. According to the principles of TCM, You‐Gui‐Wan gently reinforces the Kidney‐ Yang, supplements body essence, and replenishes the marrow. Zou‐Gui‐Wan has also been shown to affect gene expression within germ cells, whereas You‐Gui‐Wan has stronger effects on estradiol production during the differentiation of stem cells derived from human first tri‐ mester umbilical cords into oocyte‐like cells *in vitro* [55]. Another report showed that Zou‐ Gui‐Wan promptly and effectively restores ovarian function in patients with POF after failed treatment with clomiphene citrate for 8 months [56].

#### **5.4. Single Chinese herbs for infertility**

#### *5.4.1. Herba Cistanche*

Herba Cistanche, also called Rou Cong Rong in Chinese, originated from Cistanche deserticola Y.C. Ma. According to the principles of TCM, Herba Cistanche invigorates the kidney‐yin, and replenishes the vital essence and the blood. It is used as a roborant in a formula for chronic renal disease, impotence, female infertility, morbid leucorrhea, profuse menorrhagia, and senile constipation [57]. It also controls the hypothalamic‐pituitary‐adrenal (HPA) and HPG axes, which may induce a balanced and smooth sexual energy effect [58]. Herba Cistanche also has aphrodisiac effects and can increase serum levels of progesterone and testosterone, improve sperm count and sperm motility, and decrease the number of abnormal sperm [59].

#### *5.4.2. Semen Cuscutae*

Semen Cuscutae, also called Tu Si Zi in Chinese, originated from Cuscuta chinensis Lam. According to the principles of TCM, Semen Cuscutae tonifies the kidney and is also believed to arrest spontaneous emission and prevent abortion. It has a multitude of other uses, including antiaging and anti‐inflammatory, antiabortifacient, and aphrodisiac, among others [60]. One study has demonstrated that flavonoids obtained from semen cuscutae (FSCs) can be used in the treatment of ovarian endocrine dysfunction in psychologically stressed rats through increasing luteinizing hormone receptor (LHR) expression in the ovaries and estrogen recep‐ tor (ER) expression in the hippocampus, hypothalamus, and pituitaries, but without any effect on follicle‐stimulating hormone receptor (FSHR) expression in the ovaries [61]. Another study demonstrated that total flavones from semen cuscutae (TFSC) treatment can improve Kidney‐Yang deficiency symptoms by recovering the levels of testosterone and increasing androgen receptor (AR) mRNA and protein expression in the testicles and kidneys [62].

#### *5.4.3. Herba Leonuri Japonici*

Herba Leonuri Japonici, commonly called Chinese motherwort, originated from Leonurus japonicus Houtt (Labiatae). Related variants of this species include Leonurus sibiricus auct. pl., Leonurus artemisia (Lour.) S.Y. Hu., Leonurus heterophyllus sweet, and Stachys artemisia Lour [63]. According to the principles of TCM, Herba Leonuri Japonici promotes blood flow to regulate menstruation and induces diuresis to alleviate edema. It is also referred to as Yi Mu Cao in Chinese, which translates literally into "beneficial herb for mothers," and is used to manage dysmenorrhea, amenorrhea, menoxenia, lochia, edema, and other gynecological problems but is contraindicated in pregnancy due to the possibility of stimulating the uterus [63]. The aqueous extract from the aerial part of Leonurus artemisia has the potential to treat dysmenorrhea by increasing the serum progesterone level, inhibiting inflammation, relax‐ ing uterine spasms, and decreasing prostaglandin F2α (PGF2α) and prostaglandin E2 (PGE2) concentrations in uterine smooth muscle [64].
