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 Table of Contents  
CLINICAL GUIDELINES
Year : 2020  |  Volume : 4  |  Issue : 4  |  Page : 239-248

Consensus on infertility management and fertility preservation related to polycystic ovary syndrome


Reproductive Endocrinology and Fertility Preservation Section of Chinese Society on Fertility Preservation under Chinese Preventive Medicine Association

Date of Submission08-Aug-2020
Date of Decision16-Oct-2020
Date of Acceptance23-Oct-2020
Date of Web Publication31-Dec-2020

Correspondence Address:
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2096-2924.305930

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  Abstract 


There is currently no universally accepted unified diagnostic standard for infertility treatment and maternity protection related to polycystic ovary syndrome (PCOS) worldwide, and the treatment options vary greatly. To improve the understanding of PCOS-related infertility among Chinese obstetricians and gynecologists at all levels for better patient diagnosis and management, we have referred to the international expert recommendations and literature and taken into account the Chinese clinical practice to develop the “Consensus on infertility management and fertility preservation related to PCOS.”

Keywords: Diagnosis and Treatment; Expert Consensus; Fertility Protection; Infertility Treatment; Polycystic Ovary Syndclinirome


How to cite this article:
Expert Group of Consensus on Infertility Managemen and Fertility Preservation Related to Polycystic Ovary Syndrome. Consensus on infertility management and fertility preservation related to polycystic ovary syndrome. Reprod Dev Med 2020;4:239-48

How to cite this URL:
Expert Group of Consensus on Infertility Managemen and Fertility Preservation Related to Polycystic Ovary Syndrome. Consensus on infertility management and fertility preservation related to polycystic ovary syndrome. Reprod Dev Med [serial online] 2020 [cited 2021 Apr 14];4:239-48. Available from: https://www.repdevmed.org/text.asp?2020/4/4/239/305930




  Introduction Top


Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism (HA), anovulation, and polycystic ovarian morphology (PCOM). There is a large degree of difference in the manifestation of PCOS among affected individuals, and its etiology also remains unclear. PCOS is often associated with menstrual disorders, infertility, insulin resistance (IR), and metabolic disorders. Moreover, it dramatically affects women's psychological health and quality of life.[1],[2]

To improve the understanding of PCOS-related infertility among Chinese obstetricians and gynecologists at all levels for better patient diagnosis and management, we have referred to the international expert recommendations and literature and taken into account the Chinese clinical practice to develop the “Consensus on infertility management and fertility preservation related to PCOS.”


  Part I: The Concept and Definition of Polycystic Ovary Syndrome Top


The Rotterdam criteria, proposed in 2003, are currently the most widely used diagnostic criteria for PCOS. PCOS can be diagnosed in any woman presenting with at least two of the following three conditions: oligo- or anovulation, clinical and/or biochemical HA, and PCOM with 12 or more follicles in each ovary measuring 2–9 mm in diameter and/or increased ovarian volume (>10 mL) on ultrasonography. It is necessary to exclude other etiologies of HA, such as congenital adrenal hyperplasia, Cushing syndrome, ovarian or adrenal tumors, and other causes of anovulation and polycystic ovarian changes.[3]

The latest recommendation to use the Rotterdam criteria for adult women was jointly proposed by the Australian National Health and Medical Research Council, European Society of Human Reproduction and Embryology, and the American Society for Reproductive Medicine in 2018. They recommend a step-by-step approach that should be adapted to establish a PCOS diagnosis. A PCOS diagnosis can be made in the presence of clinical manifestations such as irregular menstruation and hyperandrogenemia, without ultrasound or sex hormone examination. However, in patients with irregular menstruation and no HA, serum sex hormone evaluation is required to confirm HA. Additionally, patients who only show irregular menstruation or HA should be examined for the presence of PCOM before a PCOS diagnosis is made.[4]

In 2012, the Endocrinology Group of the Society of Obstetrics and Gynecology of the Chinese Medical Association formulated the diagnostic criteria for PCOS in China, emphasizing that the presence of oligomenorrhea, amenorrhea, or irregular uterine bleeding is essential in PCOS diagnosis. Besides, patients with one of the following features can be diagnosed as “suspected PCOS:” clinically or biochemically proven HA or the presence of PCOM on ultrasound examination. Moreover, the diagnosis of “definite PCOS” can only be established after excluding other diseases that may cause HA, ovulation abnormalities, or PCOM. The purpose of this diagnostic procedure is to avoid overdiagnosis and unnecessary treatment.[5] At present, this criterion is still advocated in China for the diagnosis and treatment of PCOS.


  Part II: The Adverse Effects on Fertility Top


Oligo- and/or anovulation

  1. Abnormal uterine bleeding due to ovulatory dysfunction (AUB-O): PCOS is characterized by an irregular menstrual cycle, oligomenorrhea, hypomenorrhea, amenorrhea, heavy menstrual bleeding, and intermenstrual bleeding, which may affect a healthy sexual life. Although some patients with PCOS have regular menstrual cycles, corpus luteum dysfunction can occur because of follicular development and maturation disorders
  2. Infertility: PCOS is one of the most common endocrine disorders in women of reproductive age and the most common cause of infertility due to ovulation problems
  3. Endometrial hyperplasia, endometrial atypical hyperplasia, and endometrial cancer: Due to long-term anovulation or oligo-ovulation, the endometrium is stimulated only by estrogen without antagonism of progesterone. The endometrium remains proliferative for a long time, inducing the risk of endometrial cancer. Therefore, women with PCOS have a two- to six-fold increased risk of endometrial cancer.[4] In addition, an abnormal endometrium also affects embryo implantation.


Increased risk of spontaneous abortion

Patients with PCOS have been observed to have pathological changes such as sex hormone disorders, metabolic disorders, and obesity. Among these, high luteinizing hormone levels, HA, high insulin levels/IR, obesity, mild hyperprolactinemia, and other diseases leading to luteal-phase defects and the formation of intervillous space thrombi are considered high-risk factors for increased spontaneous abortion independently or jointly in patients with PCOS.

  1. Hyperandrogenism: HA can lead to various associated dysfunctions such as follicular dysplasia, decreased ovum quality, luteal-phase defects, and abnormal endometrial receptivity
  2. Hyperinsulinemia/IR: Hyperinsulinemia-/IR-induced abortion may be related to increased activity of plasma plasminogen activator inhibitor 1 (PAI-1) and hyper-homocysteine levels caused by insulin. High PAI-1 is closely associated with recurrent spontaneous abortion (RSA). Moreover, the high-insulin environment directly damages the oocytes and embryos
  3. Obesity: The possible mechanism by which obesity induces abortion is by aggravating IR, which, in turn, affects the quality of the oocytes and embryos, resulting in a notable decline in normal fertilization rate, clinical pregnancy rate, and live birth rate. Meanwhile, the rate of abortion increases significantly
  4. Luteal-phase deficiency (LPD): In patients with PCOS, endocrine imbalance affects the hypothalamic–pituitary–ovarian (HPO) axis function. After ovulation, the corpus luteum fails to develop normally, resulting in corpus luteum defects, which leads to LPD after pregnancy and an increased risk of pregnancy loss
  5. Thrombosis propensity: The incidence of thrombophilia in PCOS patients with RSA is as high as 70.7%,[6] which can increase the risk of pregnancy loss, especially in the early stage.


Effects of obesity on reproduction

Body mass index (BMI) is a criterion for overweight and obesity, which is commonly used to measure body fat as well. In China, a BMI of 24–28 kg/m2 is defined as overweight, while a BMI =28 kg/m2 is considered obese.[7] Obesity may lead to IR, hyperinsulinemia, HA, reproductive endocrine disorders, and severe lipid metabolism disorder.

Prepregnancy

The effects of obesity during the preconception period are mainly manifested in the following aspects:

  1. Most obese patients with PCOS have IR and hyperinsulinemia, which interfere with the secretion of gonadotropins (Gns: luteinizing hormone [LH] and follicle-stimulating hormone [FSH]) and stimulate androgen secretion in the adrenal glands and ovaries by affecting the HPO axis. HA reduces the synthesis of sex hormone-binding globulin (SHBG) in the liver and increases the free testosterone levels in the blood. These physiological changes lead to impaired follicle development and maturation, resulting in anovulatory infertility[8]
  2. HA in PCOS leads to a decrease in insulin-like growth factor-II in follicular fluid, which prevents it from amplifying the FSH-induced estradiol production and the proliferation of granulosa cells. These physiological changes further affect the formation of predominant follicles and lead to follicular arrest and eventually affect ovulation. HA also stimulates the proliferation of collagen fibers. It causes hyperplasia of the collagen fiber in the ovarian tunica albuginea, which leads to delayed rupture of the follicles, resulting in luteinized unruptured follicle syndrome (LUFS), thereby increasing the chances of infertility in patients[9]
  3. The risk of leptin resistance and hyperleptinemia is increased in obese patients with PCOS. Leptin directly acts on the pituitary gland, inhibiting LH and FSH secretion, resulting in reduced follicle recruitment and decreased follicle quality. Leptin not only inhibits follicle development and ovulation, impairing patients' fertility, but also increases IR, inducing fat synthesis and preventing its decomposition.[10]


Pregnancy

Prepregnancy obesity and obesity caused by excessive weight gain during pregnancy are included. The recommended value in China for the latter includes (1) weight gain >15 kg or (2) BMI increase =6 kg/m2.[11]

Obesity in patients with PCOS may lead to adverse consequences, including increased miscarriage rate, decreased live birth rate, increased pregnancy complications, and poor delivery outcomes. However, the exact cause and mechanism of spontaneous abortion remain unclear.[11]

Obese patients with PCOS have a higher risk of pregnancy complications, such as abnormal glucose metabolism during pregnancy and gestational hypertension (preeclampsia and pregnancy-induced hypertension). Further, the accumulation of fat causes endocrine and metabolic disorders. There is an increased secretion of insulin antagonists such as placental lactogen, estrogen, progesterone, placental insulinase, and cortisol in the middle and late pregnancies. These changes reduce the patient's insulin sensitivity and glucose tolerance, aggravate IR, and ultimately lead to islet β-cell decompensation, thereby increasing the risk of gestational diabetes mellitus.[12] High serum cholesterol levels have also been observed in obese patients with PCOS, which are deposited in the blood vessel walls to damage the vascular endothelium, causing atherosclerosis and increasing blood pressure. Pregnancy-induced hypertension leads to complications such as placental abruption, weakness in uterine contractions, fetal growth restriction, and fetal distress, increasing the risk of preterm birth.

Similarly, the recognized pathogenesis behind thrombosis during pregnancy involves hypercoagulability, blood stasis, and damage to the blood vessel walls. Obesity in PCOS patients can also increase blood viscosity. The increased risk of thrombotic disease in obese pregnant women during pregnancy and postpartum is about 1.4–5.3 times,[13] which requires more attention.

Pregnant women who are obese before pregnancy or during pregnancy have pelvic fat accumulation and abdominal wall fat thickening. Therefore, the contraction of the abdominal wall muscles and levator ani muscles is weakened, thereby weakening uterine contraction during delivery. These factors can lead to prolonged labor, delayed and blocked fetal head descent, difficulty in delivering the fetus, intrauterine distress, and increased vaginal delivery failure rate.[6]

Impact on offspring

Obesity impacts the offspring of PCOS patients in many ways. The near-term pregnancy complications can lead to fetal hypoxia, neonatal asphyxia, and stillbirth, affecting newborns' lives and health. In addition, the rate of cesarean section deliveries in obese pregnant women is relatively higher than that in normal-weight pregnant women. Compared with vaginal delivery, cesarean section is associated with an increased risk of neonatal asphyxia. Maternal obesity is also an important cause of macrosomia. As the incidence of macrosomia increases, the incidence of hypoglycemia in newborns also increases accordingly. Prepregnancy overweight and obesity significantly increase the risk of birth defects in newborns, including fetal neural tube teratogenesis, spina bifida, hydrocephalus, cardiovascular deformities, cleft lip, anal atresia, hydrocephalus, and limb deformities.

Ultimately, the offspring of obese pregnant women are at a significantly high risk of obesity and metabolic syndrome. In addition, the risks of cardiovascular disease, coronary heart disease, and Type 2 diabetes mellitus in their adulthood are also increased. Compared to the children of pregnant women with normal BMI, the children of obese pregnant women have a markedly higher risk of behavioral, cognitive, and affective disorders; emotional problems; social problems; psychological disorders; inattention; hyperactivity; autism; and stunting.

Effect of insulin resistance on fertility

IR refers to insulin's inability to promote glucose uptake of peripheral tissues and inhibit liver glucose output. IR prevalence in the general population is about 10%–25%, whereas it is about 50%–80% in PCOS women, putting the patients at risk of developing impaired glucose tolerance, cardiovascular disease, and Type 2 diabetes mellitus.[13],[14]

The impacts of IR on fertility are mainly reflected on follicular development. Additionally, it reduces female fertility by affecting embryo implantation. By inhibiting SHBG synthesis in the liver, the excess insulin will further stimulate the ovaries and adrenal glands to produce free testosterone than needed in the blood circulation, leading to the stagnation of follicular development and maturation, resulting in follicular atresia and anovulation. Conversely, increased androgen can be converted to estrone in the peripheral tissues, and decreased SHBG can also increase the levels of free estradiol. Moreover, the small follicles in the ovaries also secrete estrogen, thereby collectively causing hyperestrogenemia. Hyperestrogenemia induces an abnormal negative feedback regulation of the hypothalamus and pituitary axes, resulting in a continuous increase of LH, but not the formation of LH surge in the middle of the menstrual cycle, which promotes follicular atresia and anovulation. The absence of progesterone antagonists causes the endometrium to be affected by estrogen for a long period, resulting in hyperplastic changes, including endometrial hyperplasia and atypical endometrial hyperplasia. These endometrial abnormalities increase the risk of endometrial cancer and also impair patients' fertility.

Another critical effect of IR on fertility is the reduced efficiency of ovulation induction. For patients with PCOS, clomiphene ovulation induction is the first-line therapy. However, because of the increased probability of clomiphene resistance, its effectiveness and success rate in treating PCOS patients with IR are significantly reduced.

IR affects follicular development and has a direct detrimental effect on placental trophoblast cells in early pregnancy. Hyperinsulinemia exacerbates DNA damage of trophoblastic cells, reduces its proliferative activity, and promotes apoptosis. Therefore, IR harms the development of early embryos, leading to an increased risk of miscarriage.

The influence of adverse psychology on fertility

Most patients with PCOS have some mental and psychological problems, including depression and anxiety. There is an increased incidence of moderate/severe depressive symptoms (odds ratio, 4.18; 95% confidence interval, 2.68–6.52) among PCOS patients. However, the exact mechanism has not been fully elucidated yet.[15] Adverse psychological complications and anxiety in PCOS patients are, perhaps, caused by a variety of other problems, including acne, hirsutism, infertility, and obesity. Other potential causes of these complications include the chronic course, complexity, and frustrating therapeutic effects of PCOS.

Hirsutism seriously affects the appearance of PCOS patients. Patients often suffer from inferiority complex, which affects their sexual desire and sexual life quality. In severe cases, their social activities are reduced, which, in turn, leads to mental illness. In addition to hirsutism, acne can also damage women's appearances and increase their mental stress. Therefore, acne severity is positively correlated with the degree of anxiety, depression, and stress. Simultaneously, facial skin damage caused by acne will also increase anxiety and depression, initiating a vicious circle.

Infertility significantly affects the psychological health of patients with PCOS. Infertility is unacceptable in a culture that values lineage succession, which leads to tension and instability in marital relationships, increasing the divorce rate accordingly. Long-term depression and anxiety can cause neuroendocrine dysfunction and reduce the chances of conception. Ovulation induction therapy can achieve excellent results in most cases of infertility caused by PCOS. However, adverse psychological complications may reduce successful pregnancy rates after ovulation induction therapy and assisted reproductive technology (ART) treatment.

PCOS is a chronic disease with lifelong effects. The long-term adverse psychological state of PCOS patients aggravates endocrine abnormalities. The interaction of physiological and psychological factors worsens the patients' mental illness and physical symptomatology. People with anxiety and depression are more severely affected than noncomorbid patients, with an increased risk of recurrence and suicide. The sensitivity of the hypothalamic–pituitary–adrenal axis of patients with PCOS makes it more receptive to cortisol secretion caused by mental stress. The increase in circulating cortisol is closely related to IR, which is an important cause of Type 2 diabetes mellitus.

PCOS patients have a higher prevalence of psychological complications and sexual dysfunction, ranging from 13.3% to 62.5%,[16],[17] which affects sexual arousal, lubrication, satisfaction, and orgasm. Moreover, a negative body image caused by hirsutism, obesity, irregular menstruation, and infertility can affect their sexual behavior, resulting in a reduction in their sexual satisfaction and sexual self-worth.


  Part III: Treatment of Infertility Induced by Polycystic Ovary Syndrome Top


Lifestyle improvements and interventions

Lifestyle improvement and interventions have become a common consensus of PCOS treatment, and have been listed as the first-line treatment for PCOS.[18],[19]

Obese PCOS: Lifestyle interventions such as diet and exercise aimed at weight loss should precede drug therapy or at least simultaneously. A positive change in the cognitive behavior of PCOS patients is key to long-term weight management. If the overweight and obese PCOS patients lose 5%–10% of their body weight, it will be beneficial to their reproductive and metabolic indexes and mental health.[20] Lifestyle interventions aimed at improving diet, physical activity, and cognitive function help PCOS patients lose weight and improve IR and HA, thus restoring the ovulation function.

During the weight loss period, progesterone is beneficial in regulating the menstrual cycle and protect the endometrium. This treatment regimen not only helps patients prepare for pregnancy but also helps build confidence during recovery. The regular recommended dose of dydrogesterone, that is, 10–20 mg/day, does not inhibit ovulation.

Nonobese PCOS: For nonobese PCOS patients, lifestyle interventions aim to prevent weight gain. A high-protein diet with resistance training to enhance the muscle mass can increase the insulin sensitivity among patients and restore ovulation function.

A combination of multidisciplinary care and lifestyle intervention for the prevention or management of obesity is recommended. For obese patients, a feasible training program, such as a 30-min exercise in the morning and evening, should be employed, where the maximum heart rate should reach (140 – age)/min.[21]

Pharmacological treatment for fertility indications/ovulation induction principles

Oral medications: Indications and contraindications

After an improvement in metabolic disorders, patients who have not resumed ovulation can be administered drugs to induce ovulation. However, it is necessary to evaluate the fertility of the spouse and exclude pregnancy before starting the treatment.

Letrozole

Letrozole (LE) is a third-generation selective aromatase inhibitor and hence acts as an antiestrogen. It prevents aromatase from producing estrogen, thereby eliminating estrogen's negative feedback to the hypothalamus and pituitary gland and increasing endogenous Gn, which stimulate follicular growth and development.

LE is now the first-line ovulation induction drug for PCOS patients with anovulation or oligo-ovulation. The half-life of LE is only 45 h, which is very short compared to that of clomiphene citrate (CC). The estrogen levels can be recovered within a short time after the drug is withdrawn. There is no apparent inhibition of the endometrium, so it is more commonly used in PCOS patients who are resistant to CC. Recent studies have shown that LE ovulation treatment produces a better pregnancy rate and live birth rate than CC. There is no significant difference between the multiple pregnancy rate and the incidence of congenital defects. Importantly, the drug has an U.S. Food and Drug Administration pregnancy safety rating of D, prohibiting its use in pregnant women.


  Treatment plan Top


The treatment is started with 2.5 mg/day for 5 days starting from day 2 to 5 of the menstrual cycle or withdrawal bleeding and increased by 2.5 mg/day for the next cycle until it reaches 7.5 mg/day. Follicular development should be closely monitored after ovulation induction using LE, which is the same as CC therapy. Experts have still not agreed on a specific course of treatment required for LE ovulation therapy.

LE's common adverse effects include flushing, nausea, and fatigue, which are mainly due to the reduction of estrogen levels in the body after taking the drug. Patients with severe liver and kidney damage should be treated with caution.

Clomiphene citrate

Clomiphene citrate (CC) works by relieving estrogen's negative feedback on the hypothalamus and pituitary gland and causing Gn-releasing hormone (GnRH) release by the hypothalamus and subsequently Gn from the anterior pituitary. After treatment with CC, 60%–85% of patients start to ovulate,[22] with a pregnancy rate of about 25% and a live birth rate of about 18%.[23]


  Treatment plan Top


The treatment is started with 50 mg/day for 5 days starting from day 2 to 5 of the menstrual cycle or withdrawal bleeding and increased by 50 mg/day for the next cycle if there is no ovulation until it reaches 150 mg/day. In case of excessive stimulation of the ovaries and the development of multiple follicles, the dose can be reduced to 25 mg/day.[22]

CC's common adverse effects include mild ovarian hyperstimulation syndrome (OHSS), multiple pregnancies, hot flashes, visual disturbances, abdominal discomfort, and breast pain. The drug is contraindicated in patients with irregular vaginal bleeding of unknown cause, impaired liver function, mental depression, and thrombophlebitis. Moreover, this drug is contraindicated in patients whose imaging findings suggest a lesion in the uterus and ovaries with an uncertain nature.

Patients with PCOS should be evaluated with basal body temperature, LH test strips, or ultrasound to monitor the ovulation after treatment with LE and CC. Pregnancy usually occurs in the first 3–6 months of ovulation treatment. If three or more dominant follicles are detected with a diameter of =14 mm, it is recommended to cancel this treatment cycle. Endometrial thickening and cervical mucus secretion can be inhibited by clomiphene's antiestrogen actions, which adversely affect pregnancy. If the patient is still not pregnant after 3–4 cycles of successful ovulation induction by CC, further examinations are required to evaluate the possible reasons. Generally, the course of treatment for CC ovulation induction is not recommended for >6 months. If the treatment is ineffective after 6 months, the patients should be switched to other drugs or referred to other hospitals accredited with ART in time.

Metformin

Metformin can restore ovulation, improve pregnancy, reduce serum androgen levels, inhibit vascular endothelial growth factor production, and reduce the incidence of OHSS in PCOS patients. Therefore, the 2018 international evidence-based guidelines recommend metformin as one of the first-line treatments for PCOS. It can also be used in combination with CC.[4] In addition, metformin improves metabolism and cooperates with other drugs to improve pregnancy outcomes.

Most randomized controlled trials (RCTs) of metformin are conducted with an agonist, with metformin doses ranging from 500 mg bid to 850 mg tid until human chorionic gonadotropin (hCG) day. The use of metformin with other drugs improves the clinical pregnancy rate, live birth rate, and cycle cancellation rate and reduces the risk of OHSS. However, it has been observed that there is no significant difference in Gn levels, number of retrieved oocytes, abortion rate, and multiple birth rate.

Traditional Chinese medicine treatment

TCM recognizes the kidney-Tian Gui-Chong Ren-uterus reproductive axis disorder for the pathogenesis of PCOS. There are syndromes of kidney deficiency, hepatic stagnation, spleen deficiency, and phlegm dampness. Chinese medicine emphasizes “treatment based on syndrome differentiation” in regulating menstruation and ovulation, determining the prescriptions for treatment according to TCM syndromes.


  Kidney deficiency Top


Main syndromes: Late menstruation, oligomenorrhea, pale menstrual color, and amenorrhea. There are also abnormal vaginal bleeding, prolonged menstruation, excessive weight loss, dizziness and tinnitus, sore waist and knees, scanty menstruation, loose stools, and pale tongue with a thin coating.

Treatment: Nourishing the kidney and regulating menstruation to help pregnancy.

Prescription: Yougui pill, Zishen Yutai pill.


  Hepatic stagnation Top


Main syndromes: Infrequent menstruation, scanty menstruation, amenorrhea, menstrual disorder, constant dripping, facial acne, hirsutism, flank pain, breast tenderness, leukorrhea, yellow menstruation, yellow urine, constipation, red tongue, yellow greasy tongue coating, and pulse strings.

Treatment: Liver discharging, heat clearing, and regulating menstruation to help pregnancy.

Prescription: Modified Xiaoyao pill (Danzhi Xiaoyao pills).


  Spleen deficiency and phlegm dampness Top


Main syndromes: Late menstruation, oligomenorrhea, amenorrhea, obesity, hirsutism, dizziness, chest tightness, limb burnout, fatigue, weakness, leukorrhea, pale tongue with a fat body, thick greasy coating on the tongue surface, and slippery massive pulse.

Treatment: Strengthen the spleen and phlegm, regulate menstruation, and assist pregnancy.

Prescription: Bu Zhong Yi Qi pills, Cangfu Daotan pills (see “Wan's Gynecology:” atractylodes, Rhizoma cyperi, arisaema with Bile, Fructus aurantii, processed Pinelliae rhizome, pericarpium Citri reticulatae, poria, licorice, and ginger).

In general, patients who are advanced age and have a long course of the disease, with repeated ovulation failure and ovarian poor response, mostly present with kidney deficiency. Patients with HA, acne, and emaciated body shape usually present with liver meridian depression. Patients with IR or impaired glucose tolerance and obesity often present with spleen deficiency and phlegm dampness.

Clinically, the above-mentioned symptoms can manifest alone or together. Kidney deficiency and hepatic stagnation, spleen and kidney deficiency, and spleen deficiency can occur alone or in combination. Medication can take into account primary and secondary symptoms. In addition, periodic treatment is performed according to the patient's menstrual cycle. The Yougui pill combined with the Xiaoyao pill after menstruation and the Zishen Yutai pill after ovulation can be used in patients with kidney deficiency and liver stagnation. Patients with both spleen and kidney deficiencies should use Cangfu Daotan pills after menstruation and Zishen Yutai pills after ovulation. Patients with spleen deficiency and liver depression can use Cangfu Daotan pills in combination with Xiaoyao pills after menstruation and Bu Zhong Yi Qi granules after ovulation.

After ovulation, the occurrence of LUFS is often seen in patients with hepatic stagnation, kidney deficiency, and spleen deficiency. It is suitable to treat the patient with acupuncture and moxibustion during the follicular phase. On the 7th–16th days of the menstrual cycle, the acupuncture points are Guanyuan (Ren 4), Zhongji (Ren 3), Zigong (Ex-CA1), and Sanyinjiao (SP6). Acupuncture and moxibustion should be performed once a day or once every other day, and the needle should be kept for 30 min each time to relieve diarrhea. Pressing beans at the ear is another option for treating the following points: kidney, adrenal gland, endocrine, ovary, and Shenmen.

Gonadotropin

Indications: Resistance to LE and CC; endometrial dysplasia after LE and CC ovulation induction with a thickness of the endometrium on the hCG trigger day =6 mm; failure to get pregnant after three consecutive cycles of LE and CC with no other infertility factors.[24]

Contraindications: Patients with ovarian tumors; hyperthyroidism or adrenal dysfunction; pituitary tumors.[24]

Gn is one of the second-line treatments for PCOS infertile patients, including FSH, LH, and human menopausal gonadotropin (hMG). Current Gn preparations are diverse, such as hMG, urine-derived FSH, recombinant FSH, and recombinant LH (rLH). Gn ovulation therapy should be performed at medical centers where follicle monitoring and complications can be managed to avoid multiple pregnancy and OHSS. Because patients with PCOS using Gn are prone to ovarian hyperresponsiveness, it is recommended to use a low-dose incremental protocol. Although this treatment takes a long time to induce ovulation, the incidence of OHSS and multiple pregnancy rates has significantly reduced.

The conventional method of low-dose ascending plan: Gn administration starts from day 3 to 5 of the menstrual cycle, and the initial dose is 37.5–75.0 IU/day. During treatment, the development of follicles is monitored by ultrasound, and the dose remains unchanged when the follicles grow at a rate of 1–2 mm/day. When the follicles develop slowly, the dosage can be increased to 37.5 IU every 3 days or 75.0 IU every 5 days, until no more than three dominant follicles are detected on ultrasound. At the same time, the maximum dose is 225 IU/day. A total of 10,000 IU of hCG is injected after dominant follicles can be detected. When patients have multiple follicles or are at risk of OHSS, 5,000 IU of hCG or 0.2 mg of GnRH analog (GnRHa) is injected, and progesterone is used for luteal-phase support after ovulation.[24]

To avoid OHSS, when three or more follicles with a diameter of 17 mm or more are detected, Gn- and hCG-induced ovulation should be stopped. At the same time, this cycle should be cancelled or switched to other assisted reproductive therapy.[25]

When the levels of androgens and LH are elevated, PCOS patients treated with Gns often have an ovarian hyperresponsiveness, which generally refers to more than three follicles. At the same time, the incidences of OHSS and multiple pregnancy are also relatively higher. Pituitary downregulation by GnRHa before ovulation induction can increase the treatment success rate and reduce the incidence of OHSS, multiple pregnancy, and abortion.[26]

Laparoscopic ovarian drilling: Indications and contraindications

As a second-line treatment, it is mainly suitable for patients with ineffective LE treatment, CC resistance, intractable LH secretion, and poor follow-up conditions, where the effect of Gn treatment cannot be monitored, and laparoscopic surgery should be recommended in PCOS patients. Especially, laparoscopic ovarian drilling (LOD) is performed in patients with a BMI =34 kg/m2, LH >10 IU/L, and elevated free testosterone.

Contraindications: LOD should not be performed in patients with laparoscopic contraindication, decreased ovarian reserve, and severe pelvic adhesion.

Assisted reproductive technology

When the first- and second-line treatments fail, other ART indicators, such as Fallopian tube factors and male infertility, should be actively considered.

Intrauterine insemination

Artificial insemination with the husband's sperm and artificial insemination by donor can only be performed when laparoscopy or hysterosalpingography confirms that at least one side of the Fallopian tubes is not blocked. Intrauterine insemination (IUI) has been widely accepted as a treatment option in patients with unexplained infertility or mild oligospermia. However, the efficacy of IUI in the treatment of ovulatory infertility is unclear. There are limited data of RCTs comparing the clinical outcomes of ovulation induction and ovulation induction combined with IUI in PCOS patients. Therefore, whether or not to use IUI in combination with drugs should be based on IUI indications. The main factors include male factors, cervical factors, unexplained infertility, and sexual dysfunction.

In vitro fertilization-embryo transfer

According to the “International evidence-based guideline for the assessment and management of PCOS 2018”[4] and the World Health Organization guidelines for the management of PCOS patients with anovulatory infertility in 2016,[27] we recommend the evaluation and management flowchart [Figure 1]. Accessibility, cost, and treatment risks need to be taken into account when choosing treatment options.
Figure 1: Flowchart for the management of anovulatory infertility in polycystic ovary syndrome patients.

Click here to view


The pregnancy and live birth rates through in vitro fertilization (IVF) are similar between PCOS and non-PCOS women.[28],[29],[30] However, in patients with PCOS, follicular development is not coordinated with endometrial maturation, and there is a risk of OHSS, multiple pregnancy, increased miscarriage rate, and other complications. These risks can be controlled by changing ovulation induction strategies and trigger drugs, whole-embryo freezing, and single-embryo transfer (ET).

In PCOS patients, it is necessary to balance the efficacy and safety and carry out an individualized scheme of controlled ovarian hyperstimulation. Studies have shown that the antagonist regimen has less Gn dose, shorter duration, and lower risk of OHSS than that of the long GnRH agonist regimen. It is recommended that patients with PCOS use the GnRH antagonist regimen for controlled ovarian hyperstimulation. For other options and specific medications (such as long-term regimens and mild agonist regimens), medical professionals can refer to the “Chinese guidelines for the diagnosis and treatment of PCOS.”[19] The difference between various types of Gns is small in terms of efficacy and safety, so there is no evidence to recommend a specific one. Availability, convenient usage, and cost are factors that should be considered comprehensively. In addition, there is currently no evidence that exogenous LH supplementation can affect the IVF and intracytoplasmic sperm injection outcome of PCOS patients. Therefore, it is not recommended to add rLH during controlled ovarian hyperstimulation in PCOS patients routinely.

The trigger scheme of PCOS patients should use the lowest dose of hCG to avoid the risk of OHSS. If necessary, selective whole-embryo freezing should be considered. For PCOS patients who use an antagonist plan and undergo whole-embryo freezing to prevent OHSS, GnRHa can be used as the trigger scheme. However, corpus luteum functional defects may appear after using GnRHa, which reduces the ongoing pregnancy rate and live birth rate of the fresh transfer cycle and increases the miscarriage rate. Therefore, it is not recommended as a trigger choice for fresh embryo transfer.

The definition and effects of in vitro maturation (IVM) of an immature ovum are controversial. IVM has been offered to PCOS patients who are not sensitive to ovulation induction drugs and have experienced moderate or severe OHSS with conventional low-dose Gns.[19] However, IVF use in fresh embryo transfer cycles has been associated with a low clinical pregnancy rate, a high rate of miscarriage, and a high incidence of embryo development arrest.

Prevention and treatment of miscarriage

Prepregnancy assessment and treatment: Health and disease assessment is necessary before PCOS patients get pregnant, especially for those with a history of spontaneous abortion, IR, and obesity, which are important risk factors for spontaneous abortion. Patients with obesity, IR, or impaired glucose tolerance who have a risk of miscarriage need to be treated before pregnancy to reduce the risk of miscarriage. Consequently, progesterone should be used to regulate the menstrual cycle. It is recommended to use dydrogesterone (10–20 mg/day, 10–14 days) during the second half of the menstrual period. It does not affect the basal body temperature and ovulation. The recovery of ovulation can be monitored through the evaluation of the basal body temperature. Relevant indicators of thrombophilia should also be checked before pregnancy.

Luteal-phase support

Luteal support is recommended in PCOS women with natural or ovulation induction pregnancy. It is recommended to start luteal-phase support within 1–3 days after ovulation and continued to about 35 days after ovulation. Progesterone can be gradually withdrawn after the detection of the fetal heartbeat. Presently, oral progesterone preparations are preferred for luteal-phase support, such as dydrogesterone 20–40 mg/day and micronized progesterone capsules 200–300 mg/day. Vaginal micronized progesterone gel or progesterone injections can also be used.

Treatment for spontaneous abortion

When patients have signs of threatened miscarriage such as bleeding and lower abdominal pain, ultrasound scan and hCG testing are needed to rule out an ectopic pregnancy. These tests are also helpful in differentiating between a threatened abortion and an inevitable abortion. If the diagnosis of threatened miscarriage is confirmed, it is recommended to use progesterone for fetal protection. Oral progesterone preparations such as dydrogesterone and progesterone capsules are preferred. The first dose of dydrogesterone is 40 mg, followed by 10 mg every 8 h. During treatment, hCG and ultrasound testing should be carried out regularly. The drug is withdrawn 2 weeks after the disappearance of symptoms. Patients with RSA can continue to use the drugs 2 weeks after the last pregnancy or until the 12th–20th week. In PCOS patients, it is recommended to test for homocysteine levels after miscarriage because of an increased incidence of hyper-homocysteinemia in such patients.

Psychotherapy

Psychotherapy includes patient education, psychological counseling, cognitive-behavioral therapy, and emotional support from the family members. For patients with severe illness, specialized medical treatment is required. All patients and their families should be educated with disease-related knowledge to eliminate fear, worries, and misunderstanding. The patients' compliance can be improved by strengthening psychological counseling and the introduction of the possible problems and corresponding countermeasures. PCOS patients should be encouraged to switch to healthy lifestyles which involve having a balanced diet and exercising regularly. Group psychological counseling shall be delivered for PCOS patients and their families under psychiatrists' guidance to help them relieve the psychological burden and obtain emotional support from their families. Patients with severe anxiety and depressive symptoms should be referred to a psychiatrist and given antipsychotic treatment if necessary.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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