IVF and Reproductive Medicine in Germany

Infertility — the inability of a couple to conceive a child after 1 year of unprotected intercourse.

Infertility is defined as a disease. Frequent, unprotected intercourse leads to conception in 50% of couples within 3 months, in 75% within 6 months, and in 90% within 1 year.

Causes of infertility:

• sperm abnormalities (≥ 35% of couples);
• ovulatory dysfunction or diminished ovarian reserve (about 20%);
• tubal dysfunction and pathological changes of the pelvic organs (about 30%);
• atypical cervical mucus (≤ 5%);
• unidentified factors (about 10%).

If pregnancy does not occur after ≥ 1 year, both partners should undergo a work-up. The work-up begins with history taking, physical examination and consultations. Men are examined for spermatogenesis disorders, and women for ovulatory and tubal dysfunction, as well as for pathological changes of the pelvic organs.

Cervical mucus abnormalities

Abnormal cervical mucus  has a negative effect on fertility, inhibiting sperm penetration or promoting sperm destruction.

Pathologically altered cervical mucus:

• remains impenetrable to sperm throughout the periovulatory period;
• promotes the destruction of sperm;
• contains antisperm antibodies.

Diagnosis consists of examination for cervicitis and cervical stenosis.
Treatment involves assisted reproductive technologies (intrauterine insemination or in vitro fertilisation).

Treatment in German clinics includes intrauterine insemination and in vitro fertilisation. The use of mucus-thinning agents (for example, guaifenesin) improves the ability to conceive.

Diminished ovarian reserve (DOR)

Diminished ovarian reserve is a reduction in the quantity or quality of oocytes that leads to reduced fertility.

Ovarian reserve begins to decline at the age of 30 and declines rapidly after the age of 40. Ovarian lesions also affect the reserve. Although age is a risk factor for diminished ovarian reserve, age and DOR are predictors of infertility – and therefore of a poorer response to infertility treatment – that are independent of each other. Thus, a diminished ovarian reserve does not always mean that pregnancy is impossible.

Diagnosis consists of measuring:

• follicle-stimulating hormone (FSH) and estradiol levels for screening;
• anti-Müllerian hormone (AMH) levels and the antral follicle count (AFC).

An FSH level > 10 mIU/mL or an estradiol level < 80 pg/mL on day 3 of the menstrual cycle suggests a diminished ovarian reserve. Nevertheless, measurement of AMH and AFC is currently the best test for diagnosing a diminished ovarian reserve.
A low AMH level indicates reduced chances of pregnancy after in vitro fertilisation (IVF); pregnancy occurs rarely if the level is too low to be detected. The AFC is the total number of follicles; it is determined by observation during transvaginal ultrasound. If the AFC is low (from 3 to 10), pregnancy after IVF is less likely.

Treatment in Germany involves the use of donor eggs

If the woman is > 42 years old or her ovarian reserve is diminished,  assisted reproductive technologies using donor oocytes will be required.

Ovulatory dysfunction

Ovulatory dysfunction is abnormal, irregular (≤ 9 menstrual periods/year) or absent ovulation. Menstrual periods are often irregular or absent. The diagnosis is often made on the basis of the history or  confirmed by hormone level measurements or a series of pelvic ultrasound scans. Treatment consists of inducing ovulation with clomiphene or other drugs.

Aetiology

Most often, chronic ovulatory dysfunction in premenopausal women is caused by polycystic ovary syndrome (PCOS).
But it has many other causes, including:

• hyperprolactinaemia;
• hypothalamic dysfunction (for example, functional hypothalamic amenorrhoea);
• other diseases.

Clinical presentation

Ovulatory dysfunction is suspected when menstrual periods are absent or irregular and are not preceded by breast tenderness, bloating or abrupt mood swings (known collectively as molimina).

Diagnosis:

• menstrual history;
• basal body temperature monitoring;
• measurement of hormone levels in urine or blood serum;
• ultrasonography.

More accurate methods include:

• home test kits;
• pelvic ultrasound to monitor ovarian follicle diameter and rupture;
• measurement of serum progesterone and urinary pregnanediol glucuronide levels.

If ovulation is irregular or absent, disorders of the pituitary, hypothalamus or ovaries are looked for (for example, PCOS).

Treatment:

• clomiphene or letrozole;
• metformin may be used if the body mass index is ≥ 35;
• if clomiphene is ineffective, gonadotropins are used.

As a rule, ovulation can be induced with the drugs listed above.

Spermatogenesis disorders

Spermatogenesis disorders include disorders relating to the quantity or quality of sperm, or to its emission. Diagnosis consists of semen analysis and genetic testing. The most effective treatment is usually in vitro fertilisation with intracytoplasmic sperm injection.

Pathophysiology

Sperm abnormalities lead to:

an insufficient amount of sperm — too little (oligozoospermia) or a complete absence (azoospermia);
impaired sperm quality, such as abnormal motility or structural abnormalities.

Aetiology of spermatogenesis disorders

Spermatogenesis is adversely affected by the following factors:

• heat;
• disorders (genitourinary, endocrine or genetic);
• medicines;
• toxins.

Sperm emission disorders

Impaired sperm emission may be caused by retrograde ejaculation into the bladder.

Retrograde ejaculation often occurs for the following reasons:

• diabetes mellitus;
• neurological disorders;
• retroperitoneal dissection (for example, in Hodgkin lymphoma);
• transurethral resection of the prostate;
• obstruction of the vas deferens;
• congenital absence of both vasa deferentia or of the epididymides;
• absence of both seminal vesicles.

Almost all men with symptomatic cystic fibrosis have congenital absence of both vasa deferentia, but they are also often absent in men with mutations in the CFTR gene.

Other causes

In men with a Y-chromosome microdeletion, particularly in the AZFc region (azoospermia factor c), oligozoospermia sometimes develops through various mechanisms, depending on the specific deletion.

Another rare mechanism of infertility is the destruction or inactivation of sperm by antisperm antibodies, which are usually produced in the man’s own body.

Diagnosis

• semen analysis;
• genetic tests.

If oligozoospermia or azoospermia is detected, genetic testing is carried out in Germany. These tests include:

• standard karyotyping;
• PCR of sequence-tagged chromosomal sites (to detect microdeletions affecting the Y chromosome);
• testing for CFTR gene mutations.

Before a man with a CFTR gene mutation and his partner attempt to conceive, the woman should also be tested in order to rule out cystic fibrosis carrier status.

Additional computer-assisted assessment of sperm motility (for example, linear sperm velocity) is indicated, although it is not clear how it correlates with fertility.

Other investigations

An endocrine work-up is required if semen analysis results are abnormal, especially if the sperm concentration is < 10 million/mL. The minimum initial work-up should include:

• serum follicle-stimulating hormone (FSH) level;
• testosterone levels.

If the testosterone level is low, luteinising hormone and prolactin levels should also be measured. In men with spermatogenesis disorders the FSH level is often normal, but any increase in FSH clearly indicates a spermatogenesis disorder. If the prolactin level is elevated, testing for an anterior pituitary tumour is required; an elevated level may also indicate the presence of various medicines or recreational drugs in the body.

Specialised sperm tests, which are available at German fertility clinics, are carried out if the routine tests in both partners do not explain the cause of infertility, and also when in vitro fertilisation or gamete intrafallopian transfer is planned. They include the following:

• the immunobead test;
• the hypo-osmotic swelling test;
• the hemizona assay and the sperm penetration assay, which determine the ability of sperm
• to fertilise an egg in vitro.

If necessary, a testicular biopsy is performed to differentiate obstructive from non-obstructive azoospermia.

Treatment

• clomiphene;
• assisted reproductive technologies if clomiphene is ineffective;
• treatment of the underlying genitourinary disease.

A reduced sperm count and reduced sperm viability do not rule out pregnancy. In such cases, fertility  is improved by controlled ovarian stimulation in the woman combined with artificial insemination or assisted reproductive technologies (for example, in vitro fertilisation, intracytoplasmic sperm injection).

If the male partner does not produce enough fertile sperm, fertilisation with donor sperm  is considered.

Tubal dysfunction and pelvic lesions

Fallopian tube dysfunction is obstruction of the fallopian tubes or dysfunction of their epithelium that impairs the movement of eggs, the zygote and/or sperm; pelvic lesions are structural abnormalities that  prevent fertilisation or implantation.

Aetiology

Tubal dysfunction results from:

• pelvic inflammatory disease;
• use of an intrauterine device (rarely);
• a ruptured appendix;
• surgery on the lower abdominal organs that has resulted in adhesions;
• inflammatory diseases (for example, tuberculosis);
• ectopic pregnancy.

Pelvic lesions that lead to impaired fertility include:

• intrauterine adhesions (Asherman syndrome);
• fibroids compressing the fallopian tubes or distorting the uterine cavity
• congenital malformations;
• pelvic adhesions;
• endometriosis.

Diagnosis

• hysterosalpingography;
• sometimes sonohysterography or laparoscopy;
• assessment of fallopian tube function.

Fallopian tube obstruction

Abnormalities of the uterine cavity and tubes  are investigated by sonohysterography (introduction of isotonic sodium chloride solution into the uterus during ultrasonography). Lesions of the fallopian tubes  are additionally assessed by laparoscopy, and intrauterine lesions by hysteroscopy. Diagnosis and treatment are often carried out at the same time during laparoscopy or hysteroscopy.

Treatment

• laparoscopy and/or hysteroscopy;
• assisted reproductive techniques

During laparoscopy, pelvic adhesions can be divided or foci of pelvic endometriosis coagulated with a laser. During hysteroscopy  adhesions are divided and submucosal fibroids and polyps are removed. Assisted reproductive technologies are often necessary for women with pelvic disorders and are generally preferable.

Unexplained infertility

Infertility is usually considered unexplained if the man’s sperm is normal and the woman’s ovulation and fallopian tubes show no abnormality.

Some experts recommend continuing to investigate other causes, others recommend starting empirical treatment.

Treatment consists of controlled ovarian stimulation

Controlled ovarian stimulation (COS) stimulates the development of multiple follicles; its aim is to induce ovulation of > 1 oocyte (superovulation); COS may result in a multiple pregnancy, which is associated with increased risks and complications.

Controlled ovarian stimulation includes:

• clomiphene combined with human chorionic gonadotropin (hCG) to
• induce ovulation, for up to 3 menstrual cycles;
• intrauterine insemination within 2 days after hCG administration.

If pregnancy does not occur, gonadotropins with hCG should be used to induce ovulation, followed by intrauterine insemination.
In the luteal phase, progestogens are sometimes required to increase the likelihood of implantation. The gonadotropin dose depends on the patient’s age and ovarian reserve.

Because multiple pregnancy is a risk, doctors increasingly turn directly to in vitro fertilisation and avoid COS.

Prognosis

The pregnancy rate (65%) does not depend on whether in vitro fertilisation was performed immediately after unsuccessful treatment with a combination of clomiphene and hCG, or whether gonadotropins and intrauterine insemination were additionally used before in vitro fertilisation.

However, if in vitro fertilisation is used immediately after unsuccessful treatment with clomiphene plus hCG, women become pregnant sooner and with a far lower likelihood of a high-order multiple pregnancy (≥ 3 fetuses) than when gonadotropins are used first. Thus, if clomiphene plus hCG therapy fails, most clinicians now recommend in vitro fertilisation as the follow-up treatment. Recent data show that women > 38 years old with unexplained infertility become pregnant sooner, and costs are lower, when in vitro fertilisation is performed before COS.

Assisted reproductive technologies

Assisted reproductive technologies (ART) involve manipulation of sperm and eggs or embryos in vitro.
ART  can lead to multiple pregnancy, but the risk is much lower than with controlled ovarian stimulation. If the risk of genetic defects is high, the embryo is examined for defects before transfer and implantation (preimplantation genetic testing).

In vitro fertilisation (IVF)

IVF  is used to treat infertility associated with oligospermia, antisperm antibodies, tubal dysfunction or endometriosis, as well as unexplained infertility.

The procedure usually includes:

• controlled ovarian stimulation: clomiphene combined with gonadotropins, or gonadotropins alone; GnRH agonists or antagonists to prevent premature ovulation; once the follicles have grown sufficiently, human chorionic gonadotropin (hCG) is used for final follicular maturation and ovulation; alternatively, in women at high risk of ovarian hyperstimulation syndrome  a gonadotropin-releasing hormone (GnRH) agonist is prescribed to trigger ovulation.
• oocyte retrieval: approximately 34 hours after hCG administration, the oocytes are collected by follicular puncture, usually transvaginally under ultrasound guidance, less often via a laparoscopic approach; natural-cycle IVF (in which a single oocyte is retrieved) is sometimes offered as an alternative; the pregnancy rate with this technique is lower than when several eggs are retrieved, but it is cheaper and more often leads to success;
• fertilisation: the oocytes are inseminated in vitro; the semen sample is usually washed several times in tissue culture medium and concentrated in order to select motile sperm, which are then added to the medium containing the oocytes; at this stage intracytoplasmic sperm injection is performed, one sperm cell into each oocyte, especially if the male partner has impaired spermatogenesis.
• embryo culture: after the sperm has been added, the oocytes are cultured for 2–5 days;
• embryo transfer: 1 or several of the resulting embryos are placed in the uterine cavity, minimising the chance of a multiple pregnancy (the main risk of IVF). The number of embryos transferred is determined by the woman’s age and the likely response to IVF. Some or all of the embryos (especially if the woman is at high risk of ovarian hyperstimulation syndrome) are frozen in liquid nitrogen for transfer in a subsequent cycle. There is a growing trend towards transferring only one embryo at each transfer and freezing the remaining embryos for use in subsequent cycles if pregnancy does not occur.

The use of donor oocytes is generally recommended for women over the age of 42.

Gamete intrafallopian transfer (GIFT)

GIFT is an alternative to IVF, but is used less often because of the higher effectiveness of IVF.

GIFT is used most often if a woman has one of the following:

• unexplained infertility;
• normal tubal function with endometriosis.

Several oocytes and sperm are obtained in the same way as for IVF, but the transfer is performed transvaginally under ultrasound guidance or laparoscopically into the distal portions of the fallopian tubes, where fertilisation takes place.

Intracytoplasmic sperm injection (ICSI)

This method is useful when:

• other methods have not been successful or are unlikely to be;
• there are severe disorders of sperm function.

Oocytes are collected in the same way as for IVF. A single sperm cell is injected into each oocyte in order to avoid fertilisation by an abnormal sperm. The embryo is then cultured and transferred in the same way as in IVF.

Other methods

They include the following:

• a combination of IVF and GIFT;
• zygote intrafallopian transfer (used rarely);
• the use of donor eggs;
• transfer of frozen embryos to a surrogate mother.

Advantages of IVF in Germany

Involuntary childlessness often becomes a serious psychological and emotional problem that is hard for both partners to bear and puts their relationship at risk. Reproductive medicine is a special branch of medicine with a wide range of means at its disposal for helping nature along. The combination of reliable laboratory diagnostics, modern gentle treatment methods and psychological support for couples makes it possible to achieve considerable success in this field and to bring pregnancy closer. Germany was one of the first countries in Europe to create a dedicated registry in which all IVF (in vitro fertilisation) and ICSI (intracytoplasmic sperm injection into the egg) procedures are documented voluntarily and in detail. These data are published annually and are monitored by the German Medical Association.
Infertility treatment in Germany has a high clinical success rate. Research in recent years has enabled German scientists to develop unprecedented infertility treatments that allow couples for whom childlessness was once a verdict with no right of appeal to have a child. Today, around 60-80% of all infertile couples become parents thanks to the achievements of German medicine.
German fertility clinics and centres offer patients the full range of modern reproductive medicine in the fields of diagnostics and therapy (IVF, ICSI, PESA, TESA, TESE and others). Pregnancy cannot be guaranteed 100%, but there are means to help nature and to create favourable conditions for pregnancy. Moreover, it is not always necessary to resort to assisted reproduction straight away: sometimes drug therapy and precise timing of ovulation are enough.

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