第三⼗章

Infertility, Polycystic Ovarian Syndrome

Teacher: Wang Qingxin Department: Center of Reproductive

Medicine, Affiliated Hospital of Nantong
University
 第1节

Infertility
Key points and difficulties

Be familiar with
concept and classification, examination and diagnosis, and
treatment principles of infertility
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understand
etiology of female infertility
 Definition
• Fecundity is the probability of achieving a live birth in one menstrual cycle. Fertility as well
infertility of a women or couple is the best perceived as fecundability.
• Sterility applies an intrinsic inability to achieve pregnancy whereas infertility implies a
decrease in the ability to conceive and synonymous with sub fertility.
• Infertility is defined as the inability to conceive within one year of unprotected intercourse.
• Divided into two categories: primary and secondary. Those who have no history of pregnancy
are primary infertility and have a history of pregnancy in the past are secondary infertility.

Incidence
There is no significant difference in the incidence of infertility among different races and
regions, and the incidence is 10% to 15%.
 Causes of Infertility

• Female factor
➢ pelvic factors
➢ ovulation disorders
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• Male factor
• unexplained infertility

Cells. 2020 Apr 16;9(4):990. doi: 10.3390/cells9040990

 Female infertility
• Pelvic factors
➢ It accounts for about 25-35% of the causes of infertility
➢ Common causes：
• Tubal disease, pelvic adhesions, pelvic inflammation and their sequelae (20%)
• Uterine disease
• cervical factor (5-15%)
• endometriosis
• congenital abnormality
 Female infertility
• ovulation disorders
➢ It accounts for about 20% of the causes of infertility
➢ Common causes：
• Hypothalamic lesions: eg, hypogonadotropic anovulation；
• Pituitary disorders: such as hyperprolactinemia.
• Ovarian lesions: such as polycystic ovary syndrome, premature ovarian insufficiency, and
congenital gonadal dysgenesis, etc.
• Other endocrine diseases: such as congenital adrenal hyperplasia and thyroid dysfunction,
etc.
➢ For couples with menstrual cycle disorder, age ≥35 years, continuous decrease in ovarian antral
follicle count, and long-term unexplained infertility, the etiology of ovulatory dysfunction should
be considered first.
 Male infertility

Main cause: spermatogenesis disorders and insemination disorders

• Abnormal semen: caused by congenital or acquired causes, manifested as oligospermia,
asthenozoospermia, azoospermia, stagnation of sperm development, teratozoospermia and
simple seminal plasma abnormalities.
• Abnormal sexual function: refers to erectile dysfunction, non-ejaculation or retrograde
ejaculation caused by organic or psychological reasons, or insufficient frequency of sexual
intercourse caused by sexual arousal disorder.
• Other factors: such as immune factors, but there is currently no clear diagnostic criteria in
clinical practice.
 Unexplained infertility

• It is a state of subfertility, and the factors of both men and women cannot be ruled out,
accounting for 15% to 20% of the infertile population
• Possible causes include immune factors, recessive tubal factors, potential oocyte
abnormalities, fertilization disorders, embryonic developmental block, embryo implantation
failure, and genetic defects, etc. However, there is currently a lack of targeted detection
methods in clinical practice, and it is difficult to determine the exact cause.
Examination procedures and diagnosis of infertility
Male
Including years of infertility, sexual intercourse or ejaculation disorders, infertility-
history- related examinations and treatment history; past disease and treatment history, such as
taking mumps, diabetes; surgical history, such as vasectomy; personal history, such as exposure
to high temperature environment, smoking, Alcohol and drug use; family history

physical Including general examination and reproductive system examination

examination
It is the first choice for infertile couples. According to the WHO Laboratory Manual
semen
analysis for Testing and Handling of Human Semen (5th edition), two to three semen tests
are performed to confirm semen quality. DNA assays to test the sperm DFI

other auxiliary Includes hormone testing, reproductive ultrasound, antibody studies and genetic screening
examinations
 Female
history-taking
• History of present illness: including years of infertility, frequency of sexual life, contraception and
methods, previous pregnancy, pelvic and abdominal pain, abnormal leucorrhea, pelvic mass, history of
pelvic inflammatory disease or adnexitis, history of pelvic/abdominal surgery, etc. The presence or

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absence of mood, environmental and eating changes, excessive exercise and significant weight
changes, lactation with or without headache and visual field changes, presence or absence of
hirsutism, acne and weight changes, etc. Learn more about the relevant auxiliary examinations and
treatments.
• Menstrual history: age of menarche, periodicity and frequency, duration of menstrual period, changes
in menstrual volume, and dysmenorrhea.
• History of marriage and childbirth: marital status, history of pregnancy and childbirth, and the presence
or absence of complications during pregnancy.
 Female

history-taking
• Past history: history of tuberculosis and sexually transmitted diseases and treatment, history of
pelvic and abdominal surgery, history of autoimmune diseases, history of trauma, and history of
special illnesses in childhood, history of chronic disease medication and history of drug allergy.
• Additional medical history information: Personal history, including smoking, alcoholism, addictive
drugs, drug use, occupational, and specific environmental and toxic exposures, and family history,
especially if there is a family history of infertility and birth defects.
 Female
physical examination
• Physical development and nutritional status, height, weight, body fat distribution characteristics,
breast and thyroid conditions, etc.; pay attention to whether there are signs of excess androgen
(hirsutism, acne, acanthosis nigricans, etc.)
gynecological examination
• Vulvar development, pubic hair distribution, abnormal vaginal and cervical discharge
• Uterine size, shape, location and mobility
• Adnexal mass and tenderness; mass, tenderness and nodule in uterorectal reces
• Pelvic and abdominal wall tenderness and rebound tendernes
• pelvic mass
 Female
Infertility related auxiliary examination
• Ultrasonography: Transvaginal ultrasonography is recommended
• Hormone testing: Basic endocrine testing should be performed for
women with ovulatory disorders and age ≥35 years, AMH
• Tubal patency test: Hysterosalpingography is the preferred method for
assessing tubal patency and laparoscopy is the gold standard.
B-mode ultrasound to monitor
• other checks： follicular development
➢ Basal body temperature measurement: biphasic body temperature changes suggest the possibility of ovulation, but
cannot be used as an independent diagnostic basis
➢ Hysteroscopy, laparoscopy: for patients with uterine or pelvic abnormalities suggested by physical examination,
ultrasonography, and/or tubal patency
 Treatment of female infertility
• Lifestyle improvements and adjustments
➢ Control weight, improve nutrition, correct anemia, pay attention to age, adjust
psychology
• Correction of pelvic factors
➢ Restore anatomy, rebuild function, improve and enhance fertility
• ovulation induction
➢ According to the cause of ovulation disorder, choose appropriate ovulation
induction drugs and programs; pay attention to preventing complications
• Assisted reproductive technology
➢ Grasp the indications, apply it carefully, and improve the treatment effect
 pelvic factors
• Fallopian tube factor：
➢ If the tubal mucosa has been obstructed by tubal disease ,IVF is probably the best approach
➢ Tuboplasty, formation of a hydrosalpinx, removal of tube improves IVF outcomes
• Uterine lesions：
➢ For submucosal fibroids, larger intramural fibroids, endometrial polyps, intrauterine
adhesions, and septal uterus, etc., if the shape of the uterine cavity is significantly affected,
surgical treatment is recommended; uterine adenomyosis with significantly enlarged uterus,
GnRHa treatment can be performed for 2~3 cycles first, and assisted reproductive technology
can be used after the uterine volume shrinks to the ideal range.
• Ovarian Cancer：
➢ For non-neoplastic ovarian cysts or benign ovarian tumors, surgical excision or excision may
be considered for those with surgical indications; for ovarian masses of unknown nature, a
clear diagnosis should be made first, and surgical exploration should be performed if
necessary, and the surgical method should be determined according to the pathological results.
 pelvic factors
• endometriosis
➢ Diagnosis and treatment can be performed laparoscopically, but surgery should be performed
with caution in patients with recurrent endometriosis or significantly decreased ovarian function
➢ Moderate and severe patients can be supplemented with GnRH-a or progesterone for 3 to 6
cycles and then try to conceive naturally for 3 to 6 months. If they are still not pregnant, assisted
reproductive technology should be actively used.
• Tuberculosis of reproductive system
➢ During the active period, standard anti-tuberculosis treatment should be given first, and
contraception is required during the drug action period and drug sensitive period.
➢ For the sequelae of uterus and fallopian tubes caused by pelvic tuberculosis, it is possible to
decide whether to use assisted reproductive technology after evaluating the condition of the
endometrium
 Ovulation disorders
Commonly used drugs and programs for ovulation induction
• Clomiphene （with insulin sensitizing agents metformin）
• Letrozole
• human menopausal gonadotrophin（hMG）
• Human Chorionic Gonadotropin（hCG）
• genetic recombination FSH（rFSH）
ultrasonic
monitor hCG
Clomiphene

hMG
+--+--+--+--+--+--+--+--+--+--+--+--+--+--+--+--+--+--+--+--+--+--+--+--+--+--+--+
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28
Drugs and regimens commonly used to induce ovulation
 Unexplained Infertility

• For young women with good ovarian function, treatment can be expected, but the general
pregnancy test does not exceed 3 years
• For patients over 30 years old and the ovarian reserve begins to decline, it is recommended to
try 3-6 cycles of intrauterine insemination as a diagnostic treatment.
 第1节

Polycystic Ovarian Syndrome

 case discussion
• Chief Complaint: Menopause for 4 months and vaginal bleeding for 20 days.
• History of present illness: female, 25 years old, no menstrual cramps in the past 4 months, vaginal
bleeding started 20 days ago, the amount was more or less, and there were large blood clots, accompanied
by dizziness and fatigue. There were no symptoms such as abdominal pain and fever. Menarche at the
age of 14, irregular menstruation in the past, 7~8 days/30~60 days. Normal health. Married at the age
of 24, living together all the time, not using contraception, and having normal sex life. G0P0.
• Physical examination: pale complexion, multiple acne on the face, 2~3 long hairs on both areolas, and
thick hair on both legs. Blood pressure and pulse were normal. Gynecological examination: Married
vulva type, normal development, thick pubic hair, a lot of bright red blood in the vagina, and large blood
clots. The cervix is smooth, there is no tissue blockage in the cervix, the uterus is anterior, nulliparous
size, medium texture, good movement, no tenderness. The bilateral appendage area did not reach the
mass, tenderness (-). Auxiliary examination: urine pregnancy test: negative. B-ultrasound: The uterus
is normal in size, the endometrium is 6mm, and there are more than 12 follicles with a diameter of less
than 0.8cm in both ovaries, and no dominant follicles are found. Hormone determination: PRL10ng/L,
FSH 6IU/L, LH 15IU/L, E2 125nmol/L, T3.9nmol/L. Hemoglobin: 5.5g/L.
• Diagnosis? Treatment?
 Concept of Polycystic Ovary
Syndrome
Polycystic ovary syndrome is an endocrine disorder syndrome coexisting with reproductive
dysfunction and abnormal glucose metabolism。
• Persistent anovulation, hyperandrogenism, and insulin resistance are its important
characteristics and are the most common causes of menstrual disorders in reproductive
women, the etiology of which has not yet been elucidated。
• Current research believes that it may be caused by the interaction of certain genetic genes
and environmental factors。
• It is also called Stein-Leventhal syndrome because it was first reported by Stein and
Leventhal in 1935.
 endocrine features

• Excess androgen;
• Too much estron;
• Increased luteinizing hormone/follicle-stimulating hormone (LH/FSH) rati;
• too much insulin.
 Pathology
• Ovarian changes: bilateral ovaries increased uniformly, 2 to 5 times that of normal women, grayish-
white, with thickened and tough capsules. On the cut surface, the tunica albuginea of the ovary was
uniformly thickened, which was 2 to 4 times thicker than normal. There were ≥12 cystic follicles of
different sizes under the tunica albuginea, and the diameter was less than 1 cm. Microscopically, the
tunica albuginea was thickened and hardened, and the cortical surface was fibrotic with few cells and
prominent blood vessels. Multiple cystic dilated follicles and atretic follicles in the immature stage
were seen under the albuginea, but no signs of mature follicle formation and ovulation were found.。
• endometrial changes: due to anovulation, the endometrium is stimulated by estrogen for a long time,
showing different degrees of proliferative changes, such as simple hyperplasia, complex hyperplasia,
and even atypical hyperplasia. Long-term persistent anovulation increases risk of endometrial cancer.
 Clinical manifestations
• Abnormal menstruation: Oligomenorrhea: The length of the menstrual cycle is 35 days
to 6 months. Amenorrhea: Secondary amenorrhea (absence of menstrual period ≥ 6
months) is common; primary amenorrhea (no menarche at the age of 16) is rare. Irregular
uterine bleeding: irregularity in the menstrual cycle or period or volume。
• Infertility: Infertility in fertile women due to ovulation disorder.
• Hairy, acne: is the most common manifestation of hyperandrogenis.
• Obesity More than 50% of patients are obese (BMI ≥25), often with abdominal obesity
(waist/hip ≥0.80).
• Acanthosis nigricans Taupe-brown hyperpigmentation in skin folds such as labia, back
of neck, underarms, under breasts, and groin, with symmetrical, thickened, soft texture.
 Auxiliary examination
• Basal body temperature measurement A monophasic basal body
temperature curv.
• Ultrasonography The ovary is enlarged, the capsule echo is
enhanced, the contour is smoother, and the interstitial echo is
enhanced; one or both ovaries have more than 12 anechoic areas with
a diameter of 2-9 mm, which are arranged in a wheel shape around
the edge of the ovary, called “Necklace Sign”.
• Diagnostic curettage should be performed a few days before
menstruation or within 6 hours of menstrual cramps. The scraped
endometrium shows varying degrees of proliferative changes without
changes in the secretory period. Currently less clinically use.
• Laparoscopy The ovary is enlarged, the capsule is thickened, the Necklace Sign
surface is smooth, grayish-white, and there are new blood vessels.
Multiple follicles revealed under the capsule, no signs of ovulation.
 Auxiliary examination
• endocrine assay
➢ Serum androgens: testosterone levels usually not more than 2 times the upper limit of the
normal range, androstenedione often elevated, dehydroepiandrosterone, dehydroepiandrosterone
sulfate normal or slightly elevated.
➢ Serum FSH and LH: Serum FSH is normal or low, LH is elevated, and LH/FSH ratio is greater
than or equal to 2 to 3.
➢ Serum estrogen: Elevated estrone (E1), normal or mildly elevated estradiol (E2), and constant
at early follicular phase levels, E1/E2>1.
➢ Serum prolactin (PRL): 20% to 35% of patients with PCOS may be accompanied by a mild
increase in serum PRL.
➢ Anti-Müllerian hormone: Serum AMH is 2 to 4 times that of normal people.
 Diagnosis
risk factors Type 2 diabetes, hypertension, obesity, premature coronary heart
disease; hypersexuality, positive family history of PCOS

clinical manifestations Menstrual abnormalities

Hyperandrogen symptoms
Obesity
Acanthosis nigricans

Auxiliary examination Serum Reproductive Hormone Concentration

Pelvic Ultrasound
Measurement Basal Body Temperatur
Screening for Metabolic Complications
 Diagnostic steps
medical history Age, reasons for medical treatment, menstrual status, marital status, and whether
there are currently infertility and fertility requirements. Weight change, family
history of diabetes, obesity, high blood pressure, excess body hair, similar medical

physical examination
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conditions. Past related test results, treatment measures and effects.

Height, weight, blood pressure, breast development, galactorrhea, body hair

distribution, acanthosis nigricans, acne, etc.
Gynecological examination: vulva development and clitoral condition, whether the
vaginal mucosa is affected by estrogen, the amount of cervical mucus, whether there
is any organic disease in the uterus and appendages

Auxiliary examination see above

• Diagnostic classification

➢ Obesity and central obesity

Male obesity: obesity BMI≥25, WHR≥0.85
Abdominal obesity: waist/hip ratio (WHR)≥0.8, waist circumference >90cm

➢ With or without impaired glucose tolerance, diabetes, metabolic syndrome

• Classic PCOS patients: menstrual abnormalities and hyperandrogenism, with or
without PCOS, and severe metabolic disorders;
• No hyperandrogen PCOS: only menstrual abnormalities and PCOS, with mild
metabolic disorders;
 Treatment
menstrual cycle adjustment promote fertility

• adolescent girl;
• Women of childbearing age
• Women of childbearing age who
have no childbearing requirement; with childbearing
• postnatal care; requirements;

Protect the Prevention of Improve insulin Prevention of

endometrium heart and resistance and perinatal
prevent cerebrovascular metabolic complications and
endometrial cancer diseases abnormalities fetal-born diseases

Treatment measures for PCOS

 Treatment of PCOS patients without fertility requirements
• treatment goals
➢ In the near future: Regulate menstrual cycle, improve hirsutism and acne, control weigh;
➢ Long-term: prevention of diabetes and metabolic syndrome, prevention of endometrial
cancer, prevention of cardiovascular disease event;
• treatment method
➢ Adjust the lifestyle and control the weight;
➢ Short-acting contraceptives (COC) cyclically regulate menstruation;
➢ Progesterone cyclically regulates menstruation;
➢ Treating Insulin Resistance – Metformin;
Treatment of PCOS patients with fertility requirements

• Weight Control and Lifestyle Adjustment

• Clomiphene(CC) induces ovulation
first line
• Aromatase inhibitors induce ovulation
• insulin sensitizer

• Low-dose FSH escalating regimen to

induce ovulation second line
• Laparoscopic ovarian drilling

• Assisted Reproductive Technology - IVF / IVM third line

• Weight control is a priority step for ovulation induction in PCOS

➢ Weight loss is the number one treatment for PCOS with obesity, ideally at least 5% weight
loss;
➢ Obesity affects oocyte quality and pregnancy outcomes in addition to other risks associated
with coronary heart disease and diabetes;
➢ The occurrence of clomiphene resistance is mostly attributed to elevated free testosterone,
hyperinsulinemia, impaired glucose tolerance, and obesity. Weight control can improve
ovarian response and ovulation;
➢ Abdominal obesity in women of normal weight should be clinically noted.
• Evaluation of clinical indicators for ovulation induction in CC—first-line therapy

➢ CC is still the first-line drug for PCOS ovulation induction, which can achieve 75%-80% ovulation
rate and 22% pregnancy rate per cycle, but 15% of patients still have CC resistance, and 50% of patients
still cannot achieve pregnancy;
➢ The standard for CC resistance is set at 150 mg/day for 5 days without dominant follicle growth; this
dose results in 75% ovulation;
➢ Generally, the ovulation induction cycle should reach 6 cycles, and the live birth rate of the cumulative
6 cycles can reach 50% to 60%;
➢ Fewer side effects, multiple birth rate <10%, OHSS is rare. Problems with the endometrium and
cervical mucus have not been shown to affect pregnancy. Ultrasound monitoring and progesterone
support are not necessary.
• Evaluation of clinical indicators of gonadotropin (Gns) for ovulation induction—second-line
therapy

➢ The main side effects of

Gns application are high

 cancellation rate,
• Ovarian Drilling for PCOS - Second-Line Treatment

Ovarian Drilling for PCOS Surgical Treatment, Surgical Indications：

➢ Clomiphene-resistant PCOS patient
➢ PCOS patients with persistently elevated LH
➢ PCOS patients requiring laparoscopy
➢ PCOS patients who cannot be treated with gonadotropins
Laparoscopic ovarian drilling
• Evaluation of clinical indicators for IVF treatment of PCOS - third-line therapy

➢ There is controversy over whether to abandon the Gns regimen and proceed directly to
IVF after failure of weight control, CC or AI stimulation, or LOD therapy
➢ IVF is a reasonable option as the number of embryo transfers is manageable
➢ Reasonable IVF ovulation induction program remains controversial
➢ Clinical RCTs are needed to compare the pros and cons of FSH+GnRH-a or GnRH-a
regimens
➢ The existing literature shows that IVF treatment has similar pregnancy rates for PCOS
and non-PCOS patients, suggesting that PCOS does not involve embryo implantation
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