Gonadorelin

Advances in the Management of the Infertile Couple The options available for the treatment of infertility have substantially increased over the past decade. This article discusses the current approaches to the treatment of male-factor infertility and the recent advances in the techniques of ovulation induction and in vitro fertilization and embryo transfer.

Male-Factor Infertility

Approximately 30 percent of infertile couples have a male factor as the sole cause of infertility. Another 20 percent have a male factor in combination with a female source. Hence, in about half of infertile couples, male subfertility is a component.(1)

Evaluation of the male begins with a semen analysis on at least two occasions. Specimen collection should be preceded by a two- to three-day period of sexual abstinence. All patients with persistently abnormal test results should be evaluated by a urologist or andrologist. If pyospermia is present, it should be treated. Fertilizing ability is clearly diminished by infections of the urethra, epididymis and prostate gland.

Mild to moderate idiopathic oligoasthenospermia constitutes the vast majority of cases of male subfertility. In many of these patients, surgical or medical management aimed at increasing the number and the quality of sperm in the ejaculate is not effective.

CURRENT APPROACHES

The treatment of male subfertility is based on the hypothesis that fertilization can be enhanced by increasing the pool of highly motile, capacitated sperm and placing them in as close proximity to the oocyte as possible. Capacitated sperm are those that are prepared to undergo the acrosomal reaction, which involves the release of enzymes that allow the sperm to penetrate the zona pellucida of the oocyte. Seminal plasma contains factors that inhibit capacitation. To increase capacitation, the sperm are washed free of the seminal plasma by using specially prepared buffers. Highly motile sperm are allowed to "swim up" into the supernatant, and this fraction is then used for insemination.

Another method of separating highly motile sperm from the seminal plasma involves density gradient centrifugation with Percoll, a new medium composed of colloidal silica that is coated with polyvinyl-pyrrolidone. Because the particles in the medium are heterogeneous in size, centrifugation of Percoll results in the spontaneous formation of a density gradient.(2) Immotile sperm and other cellular debris are filtered out, allowing only the most motile sperm to settle at the bottom of the tube.

Special catheters are used for the intrauterine placement of the processed specimen. Many studies have shown that intrauterine insemination is advantageous when a hostile cervical factor limits sperm passage into the uterus.(3)

The efficacy of intrauterine insemination for other indications, such as oligospermia or unexplained infertility, is not nearly as well established. Nevertheless, the technique is widely used in these situations.

INVESTIGATIONAL APPROACHES

A catheter can be used to deposit sperm in the ampulla of the fallopian tube, the normal site of fertilization. The fallopian tube is approached through the uterus after the tubal ostium has been cannulated, either under direct visualization with a flexible fiberoptic hysteroscope or by ultrasonic guidance of the catheter through the tubal ostium. Pregnancies have recently been reported using this technique.(4) This technique could also be used for the deposition of both sperm and eggs and even zygotes.

Indications for Ovulation Induction

When a patient has amenorrhea or oligomenorrhea and infertility, the first step in the evaluation is to determine the underlying cause of abnormal menstruation. Ovulation induction can be effective in restoring fertility when ovulatory dysfunction alone is the problem. Patients with infertility may also have subtle forms of ovulatory dysfunction, such as a short or an inadequate luteal phase.

AMENORRHEA

In a woman who has previously had normal menstruation, amenorrhea is defined as the absence of periods for at least six months. Anatomic causes of amenorrhea should be excluded, especially in women who have never menstruated.

Ovarian failure (referred to as premature when it occurs before age 40) should be ruled out before ovulation induction is attempted. A follicle-stimulating hormone (FSH) level greater than 40 mIU per mL (40 IU per L) and an estradiol level less than 40 pg per mL (147 pmol per L) in the same blood sample provide confirmation of ovarian failure.

Once it is established that amenorrhea is due to reversible ovulatory dysfunction, and underlying causes have been identified and managed appropriately, treatment to restore regular ovulation can be initiated.

OLIGOMENORRHEA

Oligomenorrhea is the term used to describe infrequent menstruation. Cycle lengths are usually greater than 45 days. Infrequent ovulation and periods of unopposed estrogen are common in women with oligomenorrhea. Menstrual dysfunction in such patients is frequently referred to as chronic anovulation. Since women with oligomenorrhea most often have polycystic ovary disease, many will also have mildly to moderately elevated androgen levels.

Nearly 25 percent of women with oligo-ovulation due to polycystic ovary disease also have mild to moderate elevation of the serum prolactin level. After hyperprolactinemia has been evaluated and treated, a variety of pharmacologic agents, and even combinations of agents, can be used to restore ovulatory function and fertility.

LUTEAL PHASE DEFECTS

A defective luteal phase results from deficient secretion of progesterone by the corpus luteum or defective receptivity for progesterone by the endometrium. The term luteal phase defect has been applied both to a short interval (less than 11 days) between ovulation and menstruation and, more commonly, to a luteal phase of normal length (11 to 14 days) with below-normal progesterone levels or a reduced progesterone effect. Both result in inadequate stimulation of the endometrium. The incidence of persistent luteal phase defects in infertile women is estimated to range from 3 to 15 percent.(5)

Treatment of luteal phase defects involves replacement of progesterone, usually by means of vaginal suppositories, or the use of clomiphene (Clomid, Serophene) in high enough doses to restore the luteal phase length and adequacy.

Pharmacologic Induction of Ovulation

Four agents are available for induction or enhancement of ovulation: clomiphene; menotropins (Pergonal); gonadorelin (Factrel), a synthetic gonadotropin-releasing hormone (Gn-RH), and bromocriptine (Parlodel).

CLOMIPHENE

The effectiveness of clomiphene is related to its ability to restore appropriate endogenous release of FSH. Clomiphene is usually started on the fifth day of the cycle, following either induced or spontaneous bleeding. Initiating clomiphene therapy earlier in the cycle has been recommended to stimulate multiple follicular maturation, but this may result in an increased incidence of multiple gestation.

The initial clomiphene dosage is 50 mg daily for five days. Evidence of ovulation is obtained by determining the serum progesterone level on day 21 of the cycle. A level greater than 3 ng per mL (10 nmol per L) suggests that ovulation has occurred. The clomiphene dosage may be increased to 200 mg daily to achieve a serum progesterone concentration on day 21 of over 10 ng per mL (32 nmol per L). This level is thought to be necessary to eliminate any luteal phase deficiency that might affect implantation.(6)

Evidence of ovulation can also be obtained with vaginal ultrasonography. With the use of a 3.5 mHz vaginal probe, sequential measurement of follicular diameters and volumes can be helpful in establishing the size at which follicular rupture occurs. This size varies from 16 to 25 mm in diameter, depending on whether the follicles have been stimulated with menotropins or clomiphene. Ovulation monitoring by measuring urinary luteinizing hormone (LH) levels and performing vaginal ultrasonography in a stimulated cycle has resulted in pregnancy rates of 7 to 12 percent per cycle.(4)

Once ovulation has been achieved, the timing of intercourse or insemination can be critical to success.(7) Test kits are available for home use so that patients can monitor the onset of the LH surge. A color change indicates the LH surge. Ovulation usually occurs 12 to 24 hours following the LH peak.

In oligo-ovulatory patients with hirsutism or galactorrhea, 80 percent can be expected to ovulate and approximately 40 percent of patients become pregnant. Pregnancy will occur during the first three treatment cycles in 75 percent of patients. The multiple pregnancy rate following pharmacologic induction of ovulation is less than 10 percent.(8)

By monitoring follicular size, additional support may be provided at strategic times.

Addition of Human Chorionic Gonadotropin (HCG). The use of HCG (A.P.L., Pregnyl, Profasi, etc.) as an LH surrogate may be required in some patients who are treated with clomiphene. The rationale for administration of HCG is to replace the midcycle LH surge, which may be inadequate. When the follicular size is appropriate, HCG is given in a single dose of 5,000 to 10,000 U intramuscularly.(9)

Addition of Dexamethasone. Clomiphene may be ineffective in patients with oligo-ovulation, hirsutism and abnormal circulating androgen levels. In these patients, dexamethasone (Decadron), 0.5 mg at bedtime, can be used to blunt the nighttime peak of adrenocorticotropic hormone (ACTH), thereby decreasing the adrenal contribution to circulating androgens and thus diminishing androgen levels in the microenvironment of the ovarian follicle. Dexamethasone is given daily until pregnancy is confirmed.(10)

BROMOCRIPTINE

Elevated prolactin levels interfere with the menstrual cycle by suppressing the pulsatile secretion of Gn-RH. Bromocriptine, a dopamine agonist, inhibits pituitary production and release of prolactin. Drug therapy with bromocriptine can be initiated after the underlying cause of hyperprolactinemia or galactorrhea, or both, has been identified, and the need for surgical intervention is excluded.(11)

The usual regimen is to administer bromocriptine at a starting dose of 2.5 mg, taken at bedtime, until it is apparent from the basal body temperature curve that the patient has ovulated. The dosage may be gradually increased by 2.5 mg every three days until the prolactin level is normal. The maximum dosage is 15 mg daily. Ovulation can be expected within six weeks of the start of bromocriptine therapy. If ovulation has not occurred within two months, clomiphene may be added to the regimen.

MENOTROPINS

Approximately 30 percent of patients with evidence of clomiphene-induced ovulation but failure to conceive will become pregnant when menotropins is added to the regimen. Dosages vary and need to be individualized. The usual dose consists of two ampules, each containing 75 IU of both FSH and LH. Therapy is started on the second or third day of the cycle. Because of the risk of ovarian hyperstimulation and multiple gestations, menotropins should be administered only by physicians who can closely monitor follicular development with serum estradiol determinations or ultrasound examinations, or both.(12)

GONADOTROPIN-RELEASING HORMONE

An advantage of using the synthetic Gn-RH, gonadorelin, in some patients is the improbability of producing hyperstimulation, although multiple pregnancies have been reported. To achieve follicular growth and ovulation, the normal Gn-RH pattern of pulsatile secretion must be approximated. An automatic pump is used to deliver 5 to 20 microgram of Gn-RH intravenously or subcutaneously every 90 minutes.

HCG, 1,500 U daily for three days, is then administered at the time of the temperature rise to support the corpus luteum. The temperature rise is the signal to discontinue administration of Gn-RH.(13) This method of ovulation induction is very effective in appropriate patients, such as those with isolated gonadotropin deficiency (Kallmann's syndrome).

EMPIRIC OVARIAN SUPEROVULATION

Ovulation induction has recently been used in selected patients with no apparent ovulatory dysfunction but longstanding refractory infertility. The rationale for ovarian superovulation is that multiple ovulations will increase the probability of conception. Timed intercourse is recommended or, in appropriate cases, capacitated sperm are placed either into the uterus or directly into the peritoneal cavity. No prospective controlled study has been done to establish the relative effectiveness of this controversial approach.(14)

In Vitro Fertilization and Embryo Transfer

The most common and logical indication for in vitro fertilization and embryo transfer (IVF-ET) is the absence of fallopian tubes or the presence of significant disease of the fallopian tubes. The performance of this procedure has now been expanded to include other indications, such as unexplained infertility and male-factor infertility.(15)

The method of performing IVF-ET is summarized. The patient presents for controlled ovarian hyperstimulation early in the follicular phase of her cycle. In many cases, a Gn-RH analog (usually an agonist), such as leuprolide (Lupron), is administered during the luteal phase of the preceding menstrual cycle and continued during the next cycle to allow more controlled stimulation with other drugs.

Oocyte retrieval was originally performed during laparoscopy. Transvaginal ultrasound-guided retrieval is now commonly used. This form of retrieval requires only light sedation, which lowers the cost of the procedure and decreases the risks associated with general anesthesia.(16) The oocytes are incubated in the laboratory. The semen specimen is prepared with either the "swim-up" or density gradient technique. Following four to six hours of incubation, the eggs are ready for insemination. This delay prior to insemination has been found to improve the results.(17)

Individual oocytes are generally incubated and inseminated in separate dishes or tubes to allow individual assessment of embryo quality. An exception to this rule is made for marked oligoasthenospermia, which necessitates combining multiple oocytes in fewer dishes to achieve critical sperm densities. For normal males, insemination is usually performed with 50,000 motile sperm per oocyte. Higher sperm concentrations in normal males can lead to polyspermia. For hypofertile males, the majority of laboratories use 100,000 to 500,000 motile sperm per oocyte for insemination. Fertilization and cleavage rates are in the range of 70 and 90 percent, respectively. Fertilization rates are generally lower with male hypofertility.

TRANSFER OF EMBRYOS

The embryos are reexamined within 48 to 72 hours following aspiration to assess final embryo development. One to five embryos are then transferred into the uterus. Excess embryos may be cryopreserved. The luteal phase is usually empirically supported with progesterone injections or suppositories until the pregnancy test result is known ten to 14 days after the embryos are implanted in the uterus. Progesterone supplementation is continued for up to 12 weeks of gestation.

Gamete Intrafallopian Transfer

Gamete intrafallopian transfer (GIFT) was first described by Asch and associates.(15) This technique requires at least one normal functioning fallopian tube.(18) Following superovulation, the oocytes are harvested during laparoscopy or minilaparotomy. The fimbriated portion of the tube is then gently grasped, and a catherer is inserted into the ampullary portion of the fallopian tube. Two oocytes, mixed with 100,000 to 500,000 motile sperm, are gently injected into each fallopian tube. Clinical pregnancy rates have been reported to be as high as 30 to 40 percent per attempt, making GIFT, in the view of some infertility specialists, the procedure of choice if at least one fallopian tube is normal.

Embryo Viability

A successful IVF-ET and GIFT program generally achieves a 15 to 30 percent clinical pregnancy rate per aspiration. A 10 percent term pregnancy rate would clearly surpass the expected success rates for many of the alternative methods of treatment in this group of infertile couples. Not all centers have enjoyed such success, however. In fact, it is estimated that over half of the existing programs offering IVF-ET and GIFT have never achieved the success of one live birth.

The American Fertility Society has an IVF-ET registry, and it is hoped that all centers performing this service will voluntarily report their data. Governmental regulation has been suggested by some, because of the high cost of the procedure and the low success rate reported by most investigators. Federal guidelines may be necessary to assure quality and uniformity of these new forms of assisted reproductive technology. REFERENCES (1)Speroff L, Glass RH, Kase NG. Clinical gynecologic endocrinology and infertility. 3d ed. Baltimore: Williams & Wilkins, 1983:507. (2)Berger T, Marrs RP, Moyer DL. Comparison of techniques for selection of motile spermatozoa. Fertil Steril 1985;43:268-73. (3)Kerin J, Quinn P. Washed intrauterine insemination in the treatment of oligospermic infertility. Semin Reprod Endocrinol 1987;5(1):23-33. (4)Jansen RP, Anderson JC, Sutherland PD. Non-operative embryo transfer to the fallopian tube. N Engl J Med 1988;319:288-91. (5)Wentz AC. Physiologic and clinical considerations in luteal phase defects. Clin Obstet Gynecol 1979;22:169-85. (6)Hull MG, Savage PE, Bromham DR, Ismail AA, Morris AF. The value of a single serum progesterone measurement in the midluteal phase as a criterion of a potentially fertile cycle ("ovulation") derived from treated and untreated conception cycles. Fertil Steril 1982;37:355-60. (7)Quagliarello J, Arny M. Inaccuracy of basal body temperature charts in predicting urinary luteinizing hormone surges. Fertil Steril 1986;45:334-7. (8)Mishell DR Jr, Davajan V, eds. Infertility, contraception, and reproductive endocrinology. 2d ed. Oradel, N.J.: Medical Economics, 1986:397. (9)O'Herlihy C, Pepperell RJ, Robinson HP. Ultrasound timing of human chorionic gonadotropin administration in clomiphene-stimulated cycle. Obstet Gynecol 1982;59:40-5. (10)Lobo RA, Paul W, March CM, Granger L, Kletzky OA. Clomiphene and dexamethasone in women unresponsive to clomiphene alone. Obstet Gynecol 1982;60:497-501. (11)Crosignani PG, Ferrari C, Scarduelli C, Picciotti MC, Caldara R, Malinverni A. Spontaneous and induced pregnancies in hyperprolactinemic women. Obstet Gynecol 1981;58:708-13. (12)March CM. Therapeutic regimens and monitoring techniques for human menopausal gonadotropin administration. J Reprod Med 1978;21(3 Suppl):198-204. (13)Weinstein FG, Seibel MM, Taymor ML. Ovulation induction with subcutaneous pulsatile gonadotropin-releasing hormone: the role of supplemental human chorionic gonadotropin in the luteal phase. Fertil Steril 1984;41:546-50. (14)Dodson WC, Whitesides DB, Hughes CL Jr, Easley HA 3d, Haney AF. Superovulation with intrauterine insemination in the treatment of infertility: a possible alternative to gamete intrafallopian transfer and in vitro fertilization. Fertil Steril 1987;48:441-5. (15)Asch RH, Balmaceda JP, Ellsworth LR, Wong PC. Preliminary experiences with gamete intrafallopian transfer (GIFT). Fertil Steril 1986;45:366-71. (16)Lavy G, Restrepo-Candelo H, Diamond M, Shapiro B, Grunfeld L, DeCherney AH. Laparoscopic and transvaginal ova recovery: the effect on ova quality. Fertil Steril 1988;49:1002-6. (17)Harrison KL, Wilson LM, Breen TM, Pope AK, Cummins JM, Hennessey JF. Fertilization of human oocytes in relation to varying delay before insemination. Fertil Steril 1988;50:294-7. (18)Jones HW Jr, Acosta AA, Andrews MC, et al. Three years of in vitro fertilization at Norfolk. Fertil Steril 1984;42:826-34.

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