I. General treatment
1, the infertility of both couples to treat together, infertility is the result of the action of many etiological factors, fertility and the couple related. Therefore, the treatment of infertility should pay special attention to the joint treatment of couples. Even absolutely infertile men (i.e. those who can’t get fertility without treatment, such as ejaculation, azoospermia, etc.) should check the fertility of the female partner before the male partner undergoes treatment. Male fertility is reduced such as idiopathic or secondary oligospermia, hypospermia and aberrant spermatozoa, according to the WHO multicenter clinical study, about 26% of female spouses also have fertility problems at the same time.
2, publicity and education and preventive treatment, the occurrence of infertility is related to many factors such as life, work, environment, social and psychological, and can affect the patient’s psychology, marriage, family, etc.. Therefore, treatment should be accompanied by education about reproductive health. For more information, please refer to the section V of this guideline, “Key Points of Education for Male Infertility Patients” chapter.
In order to prevent male infertility the following points should also be focused on.
(1) Prevention of sexually transmitted diseases;
(2) Incomplete descent of the testicular blade should be managed accordingly in childhood;
(3) A safe environment, avoiding exposure to harmful factors and chemicals to the testicles;
(4) The use of treatments that impair testicular function, including certain drugs such as chemotherapy for tumors, and the preservation of the patient’s sperm for ultra-low temperature before treatment.
Second, drug treatment
The development of assisted reproduction technology has provided a new world for the treatment of male infertility, however, because it is not a treatment of the cause, there are certain limitations, such as: genetic aspects of the problem, the amplification effect on the infertile population, etc. Therefore, making and so on natural conception through drug treatment is still the pursuit of many doctors and patients.
When the cause of infertility is clearly diagnosed, and there are also therapeutic measures for the cause, the treatment effect will be more satisfactory, such as gonadotropin therapy; pulsed GnRH therapy; promotion of endogenous gonadotropin secretion; pancreatic kinase releasing enzyme therapy; testosterone rebound therapy; other endocrine disease treatment, etc.
When the cause of infertility is relatively clear, but the mechanism of infertility caused by this cause has not been elucidated, the treatment effect is often not satisfactory.
The following is a brief description of the drugs commonly used in the clinical treatment of male infertility.
1, gonadotropin treatment: the main drugs are human chorionic gonadotropin (hCG) and human menopausal gonadotropin (hMG), for: various gonadotropin secretion deficiency gonadal dysfunction (primary, secondary). Before gonadotropin replacement therapy, sex hormone testing should be routinely performed to exclude hyperprolactinemia, and MRI should be performed for suspected pituitary tumors. exogenous gonadotropins or GnRH can be used for hormone replacement therapy. hCG and hMG have been used since the 1960s to treat idiopathic oligospermia. However, the efficacy is not exact.
Treatment of acquired hypogonadotropic hypogonadism: hCG 2000 IU, subcutaneous injection, 2-3 times/week. Treatment of primary (congenital) hypogonadotropic hypogonadism: FSH is added to the above, either hMG or pure recombinant human FSH. fSH 37.5-75 IU, intramuscularly, 3 times/week * 3 months [28]. FSH is discontinued when sperm density is accepted as normal [28].
Treatment with hCG for LH deficiency alone raises intra-testicular and serum testosterone.
FSH deficiency alone can be treated with hMG or pure recombinant human FSH, and also with clomiphene.
2.Thyroxine: Thyroxine supplementation in hypothyroidism may improve fertility.
3, glucocorticoids: male infertility secondary to congenital adrenocortical hyperplasia can be treated with glucocorticoids. Glucocorticoid supplementation can reduce ACTH and androgen levels, promote gonadotropin release, intra-testicular steroid synthesis and spermatogenesis. Corticosteroid therapy is not recommended for patients with antisperm antibodies because it may lead to serious side effects and other unknown consequences.
4. Dopamine agonists (e.g., bromocriptine): Dopamine agonist bromocriptine (Bromocriptine) is used to treat hyperprolactinemia after exclusion of pituitary tumors. Dose range: 2.5-7.5 mg/d, 2-4 times/day, avoiding gastrointestinal side effects. A course of approximately 3 months is required for better results [30]. A newer drug, cabergoline, has similar efficacy to bromocriptine, but the number of doses and side effects are less.
5. Androgens and testosterone rebound therapy: androgens can inhibit spermatogenesis through the hypothalamic~pituitary~gonadal axis. Clinical treatment of male idiopathic infertility has many side effects, and the efficacy is not certain.
6. gonadotropin-releasing hormone (GnRH): GnRH is a method to increase pituitary endogenous gonadotropins in place of hCG/hMG. For the same reasons as gonadotropins, this class of drugs is not currently recommended for the treatment of idiopathic infertility.
7. Anti-estrogenic drugs (e.g., clomiphene, tamoxifen): are most commonly used in the treatment of idiopathic infertility. The mechanism is that the drug competes with estrogen receptors at the hypothalamus and pituitary levels to bind and lead to increased secretion of GnRH, FSH and LH. It mainly stimulates testosterone production by Leydig cells and secondly also promotes spermatogenesis. Anti-estrogenic drugs are relatively inexpensive and safe to take orally, however, their efficacy is still controversial.
Clomiphene is a synthetic non-steroidal estrogen with a structure similar to that of hexestrol, which exhibits a more significant estrogenic effect. It is commonly used at 50mg/d, orally. Excessive doses tend to inhibit spermatogenesis. Blood gonadotropins and testosterone must be monitored to ensure that testosterone is in the normal range. Side effects occur in about 5% but are usually mild. The efficacy is uncertain.
Tamoxifen
The estrogenic effect of Tamoxifen is weaker than that of Clomiphene, and the dose range is 10-30mg/d orally.
8, pancreatic kallikrein: It is believed that pancreatic kallikrein can stimulate sperm motility and spermatogenesis. Other mechanisms may include improving sperm metabolism, increasing testicular blood supply, stimulating Sertoli cell function, and improving the function of the gonadal output tract. The efficacy of the treatment is controversial.
9. recombinant human growth hormone (recombinant hu-man-growth, rh-GH) rh-GH can enhance testicular blade mesenchymal cell function and increase semen volume [33]. rh-GH can stimulate the release of insulin-like growth factor-1 (IGF-1), and IGF-1 can act as an autocrine/paracrine growth factor during sperm growth in . Its dose is 2-4 IU/d by subcutaneous injection. Its efficacy has not yet been convincingly studied on a large scale.
10, hexoketococine (Pentoxifyline): a phosphodiesterase inhibitor, commonly used in the treatment of vascular disease. The mechanism of its use in the treatment of idiopathic infertility is that it may improve testicular microcirculation, reduce the degradation of c AMP, increase intracellular glycolysis and ATP synthesis and therefore increase sperm viability. Commonly used dose: 1200mg/d.
11.Carnitine: It can improve sperm vitality and epididymal function, so it is used in the treatment of male infertility. Commonly used dose: 1-2g/d, 2-3 times daily, orally, for 6 months-2 years, with inexact efficacy.
12. Other drugs.
Amino acids, antibiotics, zinc, vitamins A, C, E, prostaglandin synthase inhibition, etc. have reported experience and may help to improve the parameters of sperm and conception rate, but all lack sufficient convincing power.
13.Chinese herbal medicine treatment.
According to the identification of the internal organs, qi and blood and the eight syndromes in Chinese medicine, male infertility can be divided into eight types of evidence: deficiency of kidney yang, deficiency of kidney yin, deficiency of spleen and kidney yang, deficiency of both qi and blood, liver qi stagnation, phlegm-dampness containing yang, damp-heat infusion, stasis of blood and yang.
Chinese medicine has a long history of treating male infertility and has accumulated a wealth of experience, but its efficacy still needs to be further summarized and discussed.
Surgical treatment
Male infertility is a complex and difficult problem to solve. In the diagnosis, we must first find the cause of infertility, and then carry out treatment. The treatment of male infertility has etiological treatment, and then carry out treatment. The treatment of male infertility has etiological treatment, endocrine treatment, non-specific treatment, etc. There are some patients with male infertility who have organic lesions that cannot be solved by drugs, and can only take surgical treatment. Surgical treatment indications are mainly the following categories.
1, genital malformation or developmental abnormalities: the frequent ones are cryptorchidism, urethral stricture, urethral fistula, hypospadias, epispadias, severe penile sclerosis, etc.
Testicular descent fixation is feasible for those with cryptorchidism or incomplete testicular descent. The surgery should preferably be completed before 2 years of age. When the spermatic cord or vessels are too short to be fixed in the scrotal position, testicular fixation (Fowler-Stephenson procedure) can be performed in stages. Techniques that can be applied include open surgery, laparoscopic surgery and minimally invasive surgery.
Hypospadias: Hypospadias is a common congenital malformation of the lower urinary tract and external genitalia in males. The aim of treatment is firstly, to correct the ventral flexion deformity and make the penis lift vertically; secondly, to reconstruct the urethra of the defective segment. The timing of treatment is best done before school age, i.e. between 5 and 7 years old. There are many surgical treatment methods, but the basic principles are: (1) strive to complete the surgical treatment in one phase, that is, the correction of penile hypospadias and urethroplasty in one operation; (2) complete the surgical treatment in phases, the first phase to complete the correction of penile hypospadias, the second phase to complete urethroplasty.
2, obstructive azoospermia: including obstructive azoospermia caused by congenital defects of vas deferens and seminal vesicles; vas deferens segmental dysplasia; vas deferens medical injury or ligation; post-inflammatory hard obstruction; congenital narrowing of the ejaculatory duct opening, etc. Vas deferens obstruction is one of the common causes of male infertility. Those with vasectomy obstruction such as vasectomy should be actively treated surgically.
Among all treatments for obstructive azoospermia, vasectomy and vase-epidididymal anastomosis are common and effective methods for treating obstructive azoospermia. Microsurgery has been shown to have a higher rate of recanalization.
Intratesticular obstruction: Testicular sperm extraction (TESE) is commonly used.
Testicular sperm extraction) or testicular fine needle aspiration of sperm (TESA, Testicular
sperm aspiration), obtaining TESE or TESA is suitable for almost all obstructive azoospermia.
Epididymal obstruction: CBAVD is commonly performed by percutaneous epididymal sperm aspiration (PESA, percutaneous epididymal sperpaspiration) or microscopic epididymal sperm aspiration (MESA, microscopic epididymal sperpaspiration) to obtain sperm, and the sperm obtained are generally used for ICSI treatment. Azoospermia caused by acquired acquired epididymal obstruction is feasible showing microsurgical epididymal vas deferens end-to-end or end-to-side-to-side anastomosis.
Microsurgical recanalization rates range from 60-87%, with cumulative pregnancy rates ranging from 10-43%. In terms of birth rates, microsurgical anastomosis for obstruction due to vasectomy has a higher success rate and is more economical than performing ICSI.
Proximal vasal obstruction: Proximal obstruction after vasectomy requires microsurgical vasectomy for recanalization, and vasectomy-vasectomy anastomosis can only be used for a small number of patients. The existence of secondary epididymal obstruction can be confirmed when no spermatozoa are detected in the postoperative vasectomy fluid, especially when there is toothpaste-like mucus in the proximal vasectomy fluid, and vasectomy-epididymal anastomosis should be performed.
Distal vas deferens obstruction: Extensive bilateral loss of the vas deferens due to injury from a hernia or testicular descending fixation surgery in childhood is usually not reconstructable. These cases should be treated with sperm aspiration from the proximal vas or TESE, TESA, PESA, MESA for ICSI. Extensive unilateral vas deferens absence with ipsilateral testicular atrophy may be considered for vas deferens-vas deferens anastomosis or vas deferens-epidididymal anastomosis with the contralateral side.
Ejaculatory duct obstruction: Ejaculatory duct orifice obstruction can be tried by transurethral ejaculatory ductectomy.
3, varicocele: male infertility caused by varicocele is treated by high ligation of the internal spermatic vein, laparoscopic high ligation of the internal spermatic vein or embolization treatment, etc., which can restore the fertility of some patients.
4, organic sexual dysfunction: including ED caused by severe penile trauma, pelvic fracture, vascular causative (such as venous fistula) or neurological diseases, as well as some patients with retrograde ejaculation caused by organic lesions. Indications for surgical treatment of retrograde ejaculation are those who have a history of bladder neck surgery in the past and can undergo bladder neck Y-V molding [.
IV. Assisted reproductive technology
Assisted reproductive technology (ART) refers to the use of various medical measures to conceive infertile patients, including artificial insemination, in vitro fertilization and embryo transfer. The process of conception by non-coital means requires the joint operation of clinicians and laboratory technicians and other related personnel as an important means of treating male and female infertility. Human sperm banking with ultra-low humidity preservation of sperm is also a part of assisted reproductive technology. The couple should be physically examined before the human assisted reproductive technology and must be married, as well as comply with our family planning regulations and ethical principles.
For these elements, our Ministry of Health has strict and specific documents, details of which are shown in Annex 2 – Annex 4. The main elements are described as follows.
(I), human sperm bank and sperm ultra-low temperature preservation
Human sperm banks freeze and preserve sperm for the treatment of infertility, prevention of genetic diseases and provision of reproductive insurance by establishing ultra-low temperature freezing technology [40], as an important part of male science. Depending on the density of sperm and different clinical needs, methods such as cryotubes, cryomac tubes, frozen rings or human egg zona pellucida are used [41-43]. Before freezing sperm, cryoprotectants are added, special cryogenic containers are required, and special procedures are used to freeze and store sperm in liquid nitrogen. The viability of spermatozoa decreases gradually with increasing storage time, especially with repeated exposure to room temperature. The ideal storage time should not exceed 10 years [44].
When organizing sperm donors for semen freezing and storage, this should be done in a state-approved human sperm bank and in strict accordance with the technical specifications for human sperm banks developed by the state. The sperm bank establishes a computerized management system as required to strictly manage the frozen and stored sperm. After being provided to qualified assisted reproductive technology units for use, pregnancy outcomes must be followed up to ensure that each donor’s sperm cannot impregnate more than five women [40].
Reproductive insurance is recommended for the following patients: sperm cryopreservation should be performed before chemotherapy, radiotherapy or surgical treatment due to malignant diseases, autoimmune diseases requiring chemotherapy or radiotherapy to prevent damage to testicular spermatogenic function or sperm due to chemotherapy or radiotherapy; or infertility due to inability to ejaculate after surgery. Clinical treatment of intractable azoospermia can also use transrectal electrical stimulation to collect semen for cryopreservation.
Clinical ultra-low temperature preservation of sperm or testicular tissue obtained surgically from the testis, epididymis or distal vas deferens during surgery in patients with obstructive azoospermia or non-obstructive azoospermia is recommended [45].
(ii) Artificial insemination
Artificial insemination is a therapeutic measure in which the male partner is injected into the female partner through in vitro ejaculation, after the sperm is liquefied and added to the culture fluid using the upstream method or the density gradient centrifugation method, so that the sperm and the egg are combined to induce pregnancy.
1. According to the source of sperm, there are different types of sperm.
(1) Artificial insemination of husband (AIH)
(2) Artificial insemination of donor (AID)
2.According to the different parts of the semen injected into the woman’s body, mainly divided into
(1) Artificial insemination around the cervix or in the cervical canal (ICI, Intracervical
insemination): the treated semen is slowly injected into the cervix, and the rest of the semen is placed in the vaginal vault, and this method is used for sperm donor insemination.
(2) Intra-uterine insemination (IUI, Intra-uterine insemination), intra-uterine insemination is the method with higher success rate and more frequently used in artificial insemination, the sperm of IUI is washed and optimized, and the sperm is injected into the uterine cavity with a catheter through the cervix.
(iii) In vitro fertilization-embryo transfer (IVF-ET)
This is a method of fertilization that avoids the fallopian tube. The female partner’s eggs are removed and placed in a petri dish through vaginal ultrasound, and washed and optimized male sperm are added to them 4-6 hours later to fertilize the eggs and form a fertilized egg, which takes about 48 hours to develop into a 4-8 cell embryo, and 72 hours to develop into a blastocyst that is transferred into the female partner’s uterine cavity to await implantation and conception.
The treatment consists of 4 main processes
1. Super Ovulation Promotion
The development and maturation of multiple follicles can be induced by means of medication within a controlled range, with the aim of retrieving a larger number of eggs.
2. Egg retrieval
It has the advantages of simple operation, less complications and outpatient operation, with anesthesia to reduce the patient’s fear, because multiple follicle development and removal is prone to granulosa cell loss, therefore progesterone should be used at the same time to prevent luteal insufficiency and miscarriage.
3. Fertilization
The eggs should be identified under a dissecting microscope and placed in an incubator (5% CO2, 37°C) for equilibration. 4-6 hours later, wash-optimized sperm are added, usually 100,000-150,000 sperm are needed for each egg. 20 hours after fertilization, the progenitor nucleus starts to enter the fused nucleus stage and the fertilization rate should not be less than 65%. Development to blastocyst stage, all of them are ready for embryo transfer.
4. Embryo transfer
The embryo can be transferred into the uterine cavity of the woman 48 hours or 72 hours after egg retrieval. Under the supervision of abdominal ultrasound, a special embryo transfer tube is used to absorb the embryo by the laboratory embryologist and then transferred into the uterine cavity by the attending doctor. According to the requirements of the Ministry of Health of China, the total number of embryos transferred per cycle shall not exceed 3, among which no more than 2 embryos shall be transferred in the first assisted conception cycle for women under 35 years old.
(iv) IVF-ET-derived assisted conception techniques.
1. Intra-cytoplasmic sperm injection (ICSI): a sperm is injected into the cytoplasm of a morphologically normal and mature oocyte through the zona pellucida and the oocyte membrane.
The male partner for ICSI must exclude hereditary diseases and undergo genetic counseling if necessary.
2.PGD Preimplantation genetic diagnosis (PGD, Preim-plantation genetic diagnosis) means taking some cells from the embryos fertilized in vitro for genetic monitoring, excluding embryos with disease-causing genes before transfer, and embryos with genes that can prevent genetic diseases before transfer, which can prevent the occurrence of genetic diseases. The process includes hormonal induction of superovulation, obtaining oocytes, fertilization with conventional IVF-ET or ICSI, in vitro culture to the 6-10 cell stage, taking 1-2 cells or partial cells from embryos developed to the blastocyst stage, monitoring accordingly by PCR or FISH according to the indications, and then transferring 2-3 analyzed normal embryos into the uterus.