Female infertility accounts for 10%-25% of women of childbearing age, and there is an increasing trend in recent years, and its etiology is complex and diverse. Many infertility patients are unable to clarify the cause of infertility despite the examination of hysterosalpingography (HSG), endocrine testing and ultrasound monitoring of ovulation, and thus cannot better guide the treatment. This is an introduction to the norms of infertility diagnosis and treatment.
I. Diagnostic criteria of infertility.
Textbook definition: A couple with normal sex life, who do not get pregnant after two years of cohabitation without contraception.
WHO definition: a couple with normal sex life, cohabiting without contraception for one year without pregnancy (now mostly used).
II. Infertility and Sterility.
(I) Concept
Infertility or sterility: refers to the inability to conceive, the inability to produce the next generation or the inability to get pregnant.
Infertility: refers to the actual or clinical failure to have children, and the ability to produce the next generation is limited.
(ii) Classification
Primary infertility: The woman has never been pregnant.
Secondary infertility: The woman has had pregnancies, including miscarriages and ectopic pregnancies, but not necessarily with the same partner.
Primary infertility: The man has never impregnated any woman.
Secondary infertility: The man has ever impregnated a woman, but not necessarily the current partner.
III. Epidemiology of infertility.
(i) Prevalence
United States 8.4% (1995).
Northern Europe 8.4-21% (1994)
Developing countries 10-30% (1995)
Chongqing 8.4% (2006)
China 10-15% (2007).
(II) Reasons for the increase in global infertility rate
1.Changing social status of women, delay in marriage and childbirth
2. the widespread adoption of contraceptive methods
3. the loss of control of abortion
4. the severity of environmental and ecological problems (decline in sperm quality)
5. the deterioration of economic conditions ( the gap between rich and poor and medical costs ↑).
IV. Etiology of infertility.
(i) Causes of ovulation
1. Types
Ovulation causes about 25%-30% of infertility, mainly including premature ovarian failure, polycystic ovary syndrome, gonadal dysgenesis, follicular luteinization non-rupture syndrome, hyperprolactinemia and pituitary failure, luteal insufficiency, hypogonadotropic hormone, etc.
2.Ovulation disorders (WHO typing)
Type I: reduced endogenous gonadotropins and very low endogenous estrogen levels (hypogonadotropic gonadal dysgenesis)
Type II: relatively normal or elevated gonadotropins but some endogenous estrogen
Type III: premature ovarian failure (hypergonadotropic gonadal dysgenesis).
(ii) Pelvic causes
Pelvic causes of infertility account for 30% to 40% of cases, mainly including: tubal factors (incompetence, hydrocele or obstruction); pelvic adhesions; endometriosis; uterine factors (fibroids; uterine malformations), etc.
(iii) Male causes
Male causes of infertility account for 25% to 30% of cases, mainly including: genetic diseases (sex chromosome and autosomal abnormalities); endocrine dysfunction (gonads, thyroid, pituitary, adrenal glands); reproductive organ infections (tuberculosis, epididymitis, prostatitis); sexual dysfunction (impotence, non-ejaculation, retrograde ejaculation); varicocele (moderate or severe).
Male causes of semen alterations, such as oligospermia; weak sperm; teratospermia; azoospermia (obstructive, spermatogenic disorders) Mumps, cryptorchidism, severe urinary tract infection, testicular trauma (radiation, electromagnetic waves, chemotherapy drugs), etc.
(iv) Immune causes
Infertility due to immune causes accounts for about 10% to 20%; some people just have a weak ability to conceive; most of them may be age-related; others include positive anti-sperm antibodies, positive anti-ovarian antibodies, endoheterozygosity, etc. However, it is difficult to differentiate immune from unexplained infertility with the existing examination methods.
(V) Unexplained causes
Infertility due to unknown causes accounts for about 10% to 20%.
(vi) Abnormal development of the reproductive tract or organs
Infertility caused by abnormal development of the reproductive tract or organs accounts for 0.1% to 0.1%, mainly including abnormal development of female reproductive organs (abnormal development of vulva, vagina, uterus, fallopian tubes and ovaries); abnormal development of male reproductive organs (abnormal development of penis, testes and urethra); and hermaphroditism.
V. Diagnosis.
(iii) Male causes
Male causes of infertility account for 25% to 30% of cases, including: genetic diseases (sex chromosome and autosomal abnormalities); endocrine dysfunction (gonads, thyroid, pituitary, adrenal glands); reproductive organ infections (tuberculosis, epididymitis, prostatitis); sexual dysfunction (impotence, non-ejaculation, retrograde ejaculation); varicocele (moderate or severe).
Male causes of semen alterations, such as oligospermia; weak sperm; teratospermia; azoospermia (obstructive, spermatogenic disorders) Mumps, cryptorchidism, severe urinary tract infection, testicular trauma (radiation, electromagnetic waves, chemotherapy drugs), etc.
(iv) Immune causes
Infertility due to immune causes accounts for about 10% to 20%; some people just have a weak ability to conceive; most of them may be age-related; others include positive anti-sperm antibodies, positive anti-ovarian antibodies, endoheterozygosity, etc. However, it is difficult to differentiate immune from unexplained infertility with the existing examination methods.
(V) Unexplained causes
Infertility due to unknown causes accounts for about 10% to 20%.
(vi) Abnormal development of the reproductive tract or organs
Infertility caused by abnormal development of the reproductive tract or organs accounts for 0.1% to 0.1%, mainly including abnormal development of female reproductive organs (abnormal development of vulva, vagina, uterus, fallopian tubes and ovaries); abnormal development of male reproductive organs (abnormal development of penis, testes and urethra); and hermaphroditic anomalies.
VI. Treatment
(I) Treatment of ovulation disorders
1.General treatment
(1) Change of lifestyle and rhythm.
(2) Relieving mental tension and psychological stress.
(3) Obese patients (PCOS) should increase exercise and lose 10-15% of body weight.
2.Persistent anovulation or PCOS – drug treatment
(1) Induction of ovulation to promote pregnancy: clomiphene, aromatase inhibitors (letrozole), HMG, SH, HCG.
(2) Insulin sensitizers: metformin use; other agents such as rosiglitazone.
(3) Androgen lowering: Daing-35 or other contraceptives, aminoglutethimide.
(B) Chlomiphene (CC)
1.CC Overview
(1) Mechanism: In the hypothalamus and pituitary gland, competes with E2 receptors but does not play a biological role in E2.
(2) Method: Clomiphene 50-150mg/day x 5 days from day 5 of menstruation.
(3) Monitoring: BBT or B-ultrasound or P measurement at 21 days of the cycle to determine whether ovulation has occurred.
(4) Effectiveness: 70-75% ovulation rate and 20-30% pregnancy rate. 70% pregnancy within 3 months of effective treatment.
(5) Side effects: facial flushing, ovarian enlargement, lower abdominal pain, nausea. Special attention should be paid to the occurrence of OHSS.
2. Ovulation outcome prediction
(1) Related to the type of ovarian PCO changes.
(2) BMI ↑ and poor responsiveness.
(3) The larger the ovarian volume and the higher the number of follicles, the worse the response.
(4) related to LH, FSH, E1/E2, T, A and DHAS values.
3. Reasons for low pregnancy rate
(1) LUF occurs in 30%.
(2) poor endometrial development of 7 mm in a proportion of patients
(3) thick cervical mucus.
(4) Treatment: supplementation with estradiol valerate 1 to 2 mg/day for 28 days starting on the 9th day of menstruation.
4. Causes and definition of CC resistance
5. Application of HCG
(1) Criteria for ovulation by intramuscular HCG injection: at least one follicle diameter greater than 17 mm.
(2) Criteria for non-injection of HCG: 3 or more follicles >16mm in diameter and/or 4 follicles >14mm in diameter or estrogen levels above 3000pmol/L.
(3) Criteria for cancellation of cycle: more than 7 follicles >8mm in diameter on day 8 of stimulation.
6.CC resistance treatment
(1) Primary treatment
Daine-35, metformin, daine-35 + metformin, letrozole, HMG.
(2) Secondary treatment
lap ovarian perforation, small follicle aspiration, IVM-ET.
7.CC Combination therapy
(1) CC + HCG.
dominant follicle diameter ≥ 20mm, HCG 5000~10000IU, confirm luteal support after ovulation: HCG 2000IU 1/3 day × 4 times.
(2) CC + glucocorticoid therapy: (DHA, DHAS)
Mechanism: suppressing adrenal androgen secretion, lowering LH/FSH and improving positive feedback function.
Indications: CC alone is ineffective, and patients with high adrenal androgens, DHA, DHAS ↑
Method: Prednisolone 5mg/day×10～14 days on the second day of menstruation; CC 100mg/day×5 days on the fifth day of menstruation
CC+HMG: powerful ovulation promotion method, use with caution!
(C) Aromatase inhibitors – Letrozole (letrozole)
1.Letrozole overview
Letrozole is a specific, reversible, non-steroidal aromatase inhibitor.
Ovulation-promoting mechanism: inhibits the conversion of androstenedione (A) and testosterone (T) to estrone (E1) and estradiol (E2) to promote follicular development.
Regimen: 2.5mg-5mg/day on day 3-7 of the menstrual cycle or 20mg on day 3 of the menstrual cycle.
Duration of treatment: 6 months?
2. Advantages of Letrozole
(1) Almost 100% bioavailability.
(2) Half-life of about 45 hours, transhepatic clearance.
(3) No peripheral anti-estrogenic effects, no adverse effects on estrogen target organs, does not affect endometrial thickness, can improve endometrial blood flow.
(4) Single follicle ovulation, no increase in multiple pregnancy and OHSS.
(5) 45-55% reduction in FSH dose when combined with gonadotropins.
(6) Improve ovulation and pregnancy outcome in patients with poor ovarian response.
3.Side effects of Letrozole
(1) Hot flashes.
(2) Gastrointestinal reactions (nausea, vomiting).
(3) Leg cramps.
Short-term application of letrozole to induce ovulation in healthy reproductive age women is safe. Hypothalamic, pituitary and ovarian failure without ovulation is not effective!
4. FSH / HMG ＋ HCG
(1) Low dose method: FSH/HMG, 75 IU/day until the diameter of the dominant follicle reaches 18 mm, then inject 6000-10,000 IU of HCG intramuscularly.
(2) Tapered dosing method: 150 IU-225 IU on the 5th day of menstruation, 75 IU-150 IU after 3 days, and 6000-10000 IU of HCG when the dominant follicle is ≥18mm.
(3) Pulse dosing method: HMG 150IU + 0.8ml physiological saline injection pump, 50 μl/90 min high pregnancy rate, low OHSS, but cumbersome and difficult to accept.
5.Super ovulation protocol in IVF-ET
(1) Long luteal phase regimen: GnRHa is given one week before menstruation or mid-luteal phase, and Gn is given after reaching pituitary descending regulation in 10 to 14 days.
(2) Long follicular phase regimen: GnRHa is given on the first day of menstruation and Gn is given after 15-18 days of pituitary hyporegulation.
Longer regimens are mostly used clinically!
(3) Short-cycle regimen: GnRHa is given on day 1 of the menstrual cycle and lasts until HCG day, and Gn is given on day 4 of the menstrual cycle, for those with low ovarian reserve function.
(4) Ultra-short-cycle regimen: GnRHa (short-acting) is given on day 2 of the menstrual cycle for 3-4 days and Gn on day 4 of the menstrual cycle.
The short-cycle regimen has a lower pregnancy rate and is less commonly used clinically!
6. Antagonist Cetrotide regimen
Morning dosing: Start on day 5 or 6 of ovarian stimulation with Gn (approximately 96-120 hours after the start of ovarian stimulation) and continue throughout gonadotropin treatment up to and including the day of ovulation induction.
Evening dosing: Start on day 5 of ovarian stimulation with Gn (approximately 96-108 hours after the start of ovarian stimulation) and continue throughout gonadotropin treatment until the night before ovulation is induced.
(iv) Persistent anovulation or PCOS – surgical treatment
1.Laparoscopic ovarian drilling (LOD)
Perforation → laser, electrocautery, puncture
Mechanism: LH level → decrease 24 to 48 hours after surgery
LH pulse → amplitude ↓ → testosterone and androstenedione concentration ↓ → low concentration of transient inhibitory hormone → normal response to GnRH test → ovulation
Low ovarian function has been reported, use with caution!
LOD technical requirements: monopolar electrocoagulation, 40W electrocoagulation, ≤ 7 holes per ovary, each hole contacted for 2 seconds, hole depth 2-4mm, electrocoagulation avoiding the ovarian hilum (to avoid premature ovarian failure).
2. Ovarian chordaectomy (has been used sparingly)
(v) Persistent anovulation or PCOS – fertility treatment
1.Ovulation induction + intrauterine insemination
2.In vitro fertilization – embryo transfer.
(vi) Luteal support
1.Progesterone preparation: progesterone injection 20-40mg/day or progesterone suppository 400mg/day incorporated vaginally.
2, HCG preparation: intramuscular injection of HCG 2000iu/ every other day.
3.Other progesterone preparations: oral Daphne 10mg, 3/day.
(vii) Pelvic factors
1.Tuboplasty and ostomy.
2.Tubal effusion resection.
3, pelvic adhesions separation
4, cauterization of endometriotic lesions
5, ovarian cyst debridement.
6.myomectomy for uterine fibroids.
(viii) Immune factors
1. development of a three-cycle treatment program
2. treatment to suppress autoimmune antibodies: prophylactic application of aspirin and prednisone, cyclosporine A, etc.
3. treatment of active immunity: husband or third-party lymphocyte injections.
4. treatment of passive immunity: additional immunoglobulin treatment after pregnancy.
5.Treatment of Chinese medicine: anti-sperm antibodies with high titer can be used to suppress anti-tang, etc.
6. Application of progestin (Daphne).
(ix) Endometriosis
1, laparoscopic or open surgery.
2.Medication (endometrium, GnRH, etc.)
3.Assisted reproductive technology (ART).
(J) Unexplained infertility
1.Ovulation induction + guided intercourse
2.Ovulation induction + intrauterine insemination
3.In vitro fertilization – embryo transfer.
(XI) Treatment of male infertility
1, mild oligospermia, weak spermia, teratospermia: monitoring ovulation + guiding coitus, inducing ovulation + artificial insemination.
2, moderate oligospermia, weak spermatozoa, teratospermia: in vitro fertilization – embryo transfer.
3, severe oligospermia, weak spermatozoa, teratospermia: single sperm oocyte intracytoplasmic injection.
4. azoospermia (obstructive): epididymal sperm retrieval or testicular sperm retrieval ICSI.
5. azoospermia (spermatogenic disorders): IVF-ET by sperm donation.
VII. Assisted reproductive technology (ART) indications
(A) intrauterine insemination
1, male factors: such as oligospermia, weak sperm, liquefaction abnormalities, sexual dysfunction.
2, cervical factors of infertility.
3, reproductive tract abnormalities and psychological factors leading to infertility such as inability to have intercourse.
4, immune infertility.
5, infertility of unknown origin.
(2) In vitro fertilization – embryo transfer (IVF-ET)
1. Gamete transport disorders caused by various factors in the female partner
2. Ovulation disorders.
3, endometriosis.
4. low or weak spermatozoa in the male partner
5, unexplained infertility.
6, immune infertility.
(C) Intracytoplasmic single sperm microinjection (ICSI)
1, severe oligospermia, weakness and teratogenesis
2, irreversible obstructive azoospermia.
3, spermatogenic dysfunction (not due to genetic defects).
4, immune infertility.
5, IVF failure.
6, abnormal sperm acrosome.
7, PGD is required.