Alternative, non-IVF therapies
Aldo Campana and Dilys Walker
The ultimate goal for any couple seeking treatment for infertility is to achieve a pregnancy. In the case of infertility, as with other medical conditions, the physician must first correctly identify the problem, investigate the cause of the problem, and then propose the appropriate treatment plan. The most important step in the infertility investigation is to identify the cause or causes of infertility; which is not always a simple task. To assist in this evaluation, our department follows a straight forward, step by step approach to the infertility evaluation (Campana et al., 1995).
Although in vitro fertilization (IVF) may have achieved popular notoriety, it is certainly not the only option, nor is it necessarily always the best option for treating infertility. Other treatments including timed intercourse, ovarian stimulation, and artificial insemination, are important alternatives to IVF. It is important to appreciate the relative contribution of these alternatives in helping the couple achieve a pregnancy. In our department, IVF or intracytoplasmic sperm injection (ICSI) is responsible for only about 20% of pregnancies among infertile couples. This means that in most cases, pregnancies are obtained through non-IVF therapies. It is interesting to note that more than 20% of all pregnancies are spontaneous, achieved during the course of infertility investigations (table 1).
The occurrence of spontaneous pregnancies during the infertility work up is well known and has been documented in a study conducted by the World Health Organization (WHO), with pregnancy rates ranging from 12 to 16% (Cates et al., 1988). Another recently published study (Gleicher et al., 1996) showed that the cumulative rate of spontaneous pregnancies in women seeking infertility treatment was 20% after one year. This data illustrates the importance of a thorough investigation that can be helpful not only for determining a diagnosis, but also may result in a pregnancy.
What are the possible explanations for spontaneous pregnancies occurring during the infertility evaluation? The first explanation lies in the fact that, in the general population, monthly fecundability is variable and depends upon a variety of factors. The woman's age is a typical example. For a woman throughout her 30's, there is natural progressive decline in fecundability. (Frank et al., 1994). This decline explains why a woman in her later reproductive years might become spontaneously pregnant after more than one year of unprotected intercourse. One year is generally accepted as the cut off for the period of time after which a couple is considered infertile. Another important issue related to the occurrence of these spontaneous pregnancies is the inherent variability of each couple's fertility. For example, sperm quality is influenced by many factors such as stress, illness, or medical treatments (Campana et al., 1995). Therefore, temporary, transient abnormalities in sperm quality occur often. The same is true for the ovulatory function. Furthermore, spontaneous pregnancies occurring after some years of infertility may be explained by a number of «subfertility» factors, affecting one or both partners. And finally, perhaps the most important explanation for these spontaneous pregnancies is that they may be the result of careful counselling and dialogue between the couple and physician.
Treatment of female infertility
Female infertility can be due to a tuboperitoneal, ovulatory, uterine, cervical or vulvovaginal factor (Campana et al., 1995). The most frequently encountered female factor is tuboperitoneal, followed by the ovulatory. Uterine and cervical factors are less frequent, and a vulvovaginal factor is rarely identified as the cause of infertility.
Tuboperitoneal factor refers to damage to the fallopian tubes and, or intraperitoneal adhesions and scarring. This problem is usually caused by prior pelvic infection, endometriosis, or surgery and often results in partial or complete blockage of the fallopian tubes, making spontaneous pregnancy unlikely. Some cases of tuboperitoneal factor infertility can be successfully treated by surgery. Most of these surgeries are performed by laparoscopy, with their success dependent upon the underlying severity of the problem. The success of such treatments depends on the underlying severity of the problem. In our experience, the pregnancy rate after tubal surgery is about 30%. In the majority of cases however, a tubal factor cannot be successfully treated by surgery. It is for these cases that IVF provides the best therapeutic alternative.
Ovulatory disorders account for about 15% of all infertility factors (Speroff et al., 1994). In some cases it is possible to treat the cause of the disorder and in this way restore the normal ovulatory cycle (see table 2). These disorders may originate outside the hypothalamic pituitary axis and therefore may require correcting other associated endocrinologic problems, behavioral changes, or surgery. After ruling out or treating other problems, a pharmacologic treatment is indicated to induce ovulation. The choice of hormone therapy depends on the underlying cause of the disorder or imbalance (table 3). Clomiphene citrate is the most commonly used drug to induce ovulation and acts by stimulating the hypothalamic release of GnRH. In some cases, clomiphene is not effective in inducing ovulation and other drugs have to be considered. Gonadotropins are often the next line of therapy and directly stimulate ovarian function. All of these treatments have important side-effects, but the most important complication, at least for clomiphene and gonadotropin therapy, is the risk of multiple pregnancy: This risk is about 5% for clomiphene, and 10 to 40% for gonadotropin therapy, depending on the quality of the monitoring and good medical judgment (Speroff et al., 1994).
Overall, how effective is hormone therapy in achieving a pregnancy? According to various studies, patients undergoing clomiphene treatment have cumulative pregnancy rates ranging from 25 to 49% (Hammond, 1996). The cumulative pregnancy rates for gonadotropin therapy range from 40 to 90%, and again, depend on the underlying cause of the ovulatory disorder (Speroff et al., 1994).
Uterine causes for infertility include congenital anomalies, submucous fibroids, uterine polyps, and intrauterine synechiae (Campana et al., 1995). These uterine factors can be a cause of both infertility and recurrent spontaneous abortion. All of these conditions may be successfully treated by hysteroscopic surgery.
Cervical factor infertility accounts for about 5% of all infertility cases and refers primarily to abnormalities in the cervical mucus. In case of a cervical infection, antibiotic treatment is advised. In most cases, however, the quality of the cervical mucus cannot be improved by medical treatment, and intrauterine insemination is considered the treatment of choice (Campana et al., 1996).
Treatment of male infertility
If the semen analysis is abnormal, further investigations should be performed according to the specific type of sperm anomaly: azoospermia, aspermia or another sperm abnormality (Campana et al., 1995). Azoospermia may be due to a primary testicular failure, a hypogonadotropic hypogonadism, or to an obstruction of seminal pathways. Primary testicular failure is a condition which cannot be reversed by medical or surgical treatment. In some cases, it is possible to aspirate spermatozoa directly from the testes, and to achieve fertilization and subsequent pregnancy by ICSI (Silber et al., 1995). In contrast, hypogonadotropic hypogonadism can be treated with gonadotropin therapy (Martin-du Pan & Campana, 1993). Obstructive azoospermia can be treated in some cases by surgery, or, as an alternative, by sperm aspiration from the epididymis with subsequent ICSI (Silber et al., 1995). As is the case for azoospermia, other categories of semen abnormalities such as oligozoospermia, asthenozoospermia, and teratozoospermia require an etiologic diagnosis before suggesting either a medical or surgical treatment. In some cases a medical or surgical treatment may improve sperm quality. For example, prostatitis causes sperm abnormalities that may be successfully treated with a combination of antibiotics and anti-inflammatory agents. Patients with varicoceles may benefit from surgical revision. The most important therapeutic approaches for male infertility are listed in table 4.
Unfortunately, most causes of sperm abnormalities cannot be significantly improved by either medical or surgical treatment. In such cases, it is important to accurately quantify the number of normal spermatozoa present in the ejaculate. This will allow one to estimate the chances of obtaining a pregnancy with artificial insemination. A recent evaluation of the insemination program at our hospital provides some important information (Campana et al., 1996). Pregnancy rates for insemination cycles are directly related to both sperm counts and the age of the woman. Table 5 illustrates the dramatic drop in pregnancy rates when the woman is over the age of 40. Another important factor in predicting the success of insemination is the number of motile spermatozoa (table 6). In our study the pregnancy rate was significantly lower when less than 0.5 million total motile sperm were used for the insemination. Even when the number of total motile sperm inseminated was between 0.5 and 1 million, pregnancy rates tended to be lower than when more than 1 million motile sperm could be used. Consequently, couples in which the male displayed severe asthenozoospermia or a combination of oligozoospermia and asthenozoospermia with a total motile sperm count of less than 1 million sperm, failed to obtain a pregnancy.
Treatment of unexplained infertility
The prevalence of unexplained infertility ranges from 3 to 14% of all investigated infertility cases (Cates et al., 1988). Many empiric treatments have been proposed for unexplained infertility, the most popular one is pharmacologic treatment with clomiphene. According to the results of randomized studies clomiphene is more effective than placebo, with a cumulative pregnancy rate of about 20% after 3 or 4 treatment cycles (Fisch et al., 1989; Glazener et al., 1990). Insemination both with and without ovarian stimulation has also been suggested for the treatment of unexplained infertility. Overall, the highest pregnancy rates for unexplained infertility are reported in cycles treated with clomiphene, with or without insemination, or in gonadotropin stimulated cycles with or without insemination. (Nulsen et al., 1993).
Conclusion
Although some may believe that IVF is the "ultimate" endpoint, or "gold standard" in infertility treatment, we have seen how this may not be the most appropriate choice. However, there is also another important consideration in this day and age of rising medical costs. Clearly, the economic impact of IVF with both direct and indirect costs must be acknowledged. Considering only direct costs, the price of IVF is more than 10X that of clomiphene treatment or insemination. The indirect costs (premature babies, complications related to the procedure, etc.) are also very important and must certainly be added to the direct costs for a correct assessment of overall costs attributable to IVF. It is then up to society as a whole to determine the relative costs and benefits for IVF in the context of other therapeutic options.
References
- Campana A, de Agostini A, Bischof P, Tawfik E, Mastrorilli A (1995) Evaluation of infertility. Hum Reprod Update, 1: 586-606.
- Campana A, Sakkas D, Stalberg A, Bianchi PG, Comte I, Pache Th, Walker D (1996) Intrauterine insemination: evaluation of the results according to the woman’s age, sperm quality, total sperm count per insemination, and life table analysis. Hum Reprod, 11: 732-736.
- Cates W, Farley TMM, Rowe PJ (1988) Patterns of infertility in the developed and developing wolds. In: Diagnosis and treatment of infertility. Eds.: PJ Rowe, EM Vikhlyaeva. Hans Huber Publishers, Toronto, p. 57-67.
- Fisch P; Casper RF; Brown SE; Wrixon W; Collins JA; Reid RL; Simpson C (1989) Unexplained infertility: evaluation of treatment with clomiphene citrate and human chorionic gonadotropin. Fertil Steril, 51: 828-33.
- Frank O, Bianchi PG, Campana A (1994) The end of fertility: Age, fecundity and fecundability in women. J Biosoc Sci, 26: 349-368.
- Glazener CM; Coulson C; Lambert PA; Watt EM; Hinton RA; Kelly NG; Hull MG (1990) Clomiphene treatment for women with unexplained infertility: placebo-controlled study of hormonal responses and conception rates. Gynecol Endocrinol, 4: 75-83.
- Gleicher N, VanderLaan B; Pratt D; Karande V (1996) Background pregnancy rates in an infertile population. Hum Reprod, 11: 1011-1012.
- Hammond MG (1996) Induction of ovulation with clomiphene citrate. In: Gynecology and obstetrics. Vol. 5. Ed.: JJ Sciarra. Lippincott-Raven Publishers, Philadelphia, Chap. 68.
- Martin-du Pan RC, Campana A (1993) Physiopathology of spermatogenic arrest. Fertil Steril, 60: 937-946.
- Nulsen JC; Walsh S; Dumez S; Metzger DA (1993) A randomized and longitudinal study of human menopausal gonadotropin with intrauterine insemination in the treatment of infertility. Obstet Gynecol, 82: 780-786.
- Silber SJ; Nagy Z; Liu J; Tournaye H; Lissens W; Ferec C; Liebaers I; Devroey P; Van Steirteghem AC (1995) The use of epididymal and testicular spermatozoa for intracytoplasmic sperm injection: the genetic implications for male infertility. Hum Reprod, 10: 2031-2043.
- Speroff L, Glass RH, Kase NG (1994) Clinical gynecologic endocrinology and infertility. Fifth edition. Williams & Wilkins, Baltimore.
Table 1. Infertility treatments and subsequent pregnancies (N=444).
| Treatment | Pregnancies | |
| No. | % | |
| Spontaneous pregnancies | 99 | 22.3 |
| Hormone treatment | ||
| Female | 56 | 12.6 |
| Male | 5 | 1.1 |
| Antibiotic treatment of the couple | 42 | 9.5 |
| Surgical treatment | ||
| Female | 38 | 8.6 |
| Male | 2 | 0.5 |
| Artificial insemination with husband semen | 58 | 13.1 |
| Artificial insemination with donor semen | 56 | 12.6 |
| IVF or ICSI | 80 | 18.0 |
| Pregnancies after IVF or AIH failure | 8 | 1.8 |
Table 2. Etiologic treatment of ovulatory disorders.
- Treatment of extragonadal endocrinopathy
- Adrenal dysfunction
- Thyroid dysfunction
- Psychotherapy in cases of psychogenic amenorrhea
- Dietary means
- Weight loss
- Obesity
- Moderation of exercise and fulfillment of optimal nutritional needs in exercise-related amenorrhea
- Change of treatment in case of iatrogenic ovulatory disorders
- Surgical treatment
- Prolactinoma
- Craniopharyngioma
Table 3. Symptomatic treatment of amenorrhea and infertility.
| Etiology | Treatment |
| Hypogonadotropic normoprolactinemic amenorrhea, failure of estrogen production | Gonadotropin treatment Pulsatile GnRH |
| Polycystic ovary syndrome and hypothalamic amenorrhea with estrogen production | Clomiphene citrate Gonadotropin treatment Pulsatile GnRH |
| Hyperprolactinemic amenorrhea | Dopamine agonists |
Table 4. Medical and surgical treatment of male infertility.
| Infertility causes | Treatment |
| Hypogonadotropic hypogonadism | Gonadotropin therapy GnRH therapy |
| Prolactinoma | Surgical or medical treatment |
| Epididymal or vas deferens obstruction | Microsurgical anastomosis |
| Ejaculatory duct obstruction | Endoscopic surgery |
| Epididymal cyst | Microsurgical resection |
| Varicocele | Surgical treatment Transvenous embolization of the internal spermatic vein |
| Prostatitis, vesiculitis | Antibiotics, anti-inflammatory drugs |
| Immunologic infertility | Corticosteroids |
| Erectile dysfunction | Sex therapy |
| Retrograde ejaculation | Sympathicomimetics |
| Anejaculation | Sex therapy Electroejaculation Parasympathicomimetics |
| Premature ejaculation | Sex therapy |
Table 5. Pregnancy rates (a) per patient and (b) per insemination cycle with reference to the age of the woman.
(a)
| Age (years) | No. of patients | No. of pregnancies | Pregnancy rate per patient (%) | Mean no. of cycles per patient |
| <30 | 55 | 9 | 16.4 | 2.6 |
| 30-34 | 116 | 25 | 21.6 | 3.1 |
| 35-39 | 104 | 23 | 22.1 | 3.6 |
| 40-44 | 47 | 5 | 10.6 | 4.3 |
| >44 | 10 | 0 | 0.0 | 3.6 |
| Total | 332 | 62 | 18.7 | 3.4 |
(b)
| Age (years) | No. of cycles | No. of pregnancies | Pregnancy rate per cycle (%) |
| <30 | 143 | 9 | 6.3 |
| 30-34 | 357 | 25 | 7.0 |
| 35-39 | 377 | 23 | 6.1 |
| 40-44 | 202 | 5 | 2.5 |
| >44 | 36 | 0 | 0.0 |
| Total | 1115 | 62 | 5.6 |
Table 6. Pregnancy rates after intrauterine insemination with respect to (a) total motile sperm count per insemination and (b) total motile sperm count before sperm preparation.
(a)
| Total motile sperm count per insemination (millions) | No. of cycles | No. of pregnancies | Pregnancy rate per cycle (%) |
| ≤0.5 | 164 | 3 | 1.8 |
| 0.51 - 1.0 | 116 | 3 | 2.6 |
| 1.1 - 5.0 | 520 | 37 | 7.1 a |
| >5.0 | 315 | 19 | 6.0 b |
| Total | 1115 | 62 | 5.6 |
a : c 2=5.4, P=0.02 compared to the <0.5 group
b : c 2=3.6, P=0.06 compared to the <0.5 group
(b)
| Total motile sperm count (millions) | No. of cycles | No. of pregnancies | Pregnancy rate per cycle (%) |
| ≤1.0 | 37 | 0 | 0.0 |
| 1.1 - 10.0 | 209 | 8 | 3.8 |
| 10.1 - 20.0 | 169 | 8 | 4.7 |
| 20.1 - 40.0 | 170 | 15 | 8.8 |
| 40.1 - 100.0 | 259 | 9 | 3.5 |
| >100.0 | 271 | 22 | 8.1 |
| Total | 1115 | 62 | 5.6 |