Current Development

The theory and practice of ovulation induction with gonadotropin-releasing hormone

Robert L. Reid, MD, Ruth Fretts, MD, and Dean A. Van Vugt, PhD

Kingston, Ontario, Canada

Gonadotropin-releasing hormone therapy has undergone sufficient basic and clinical investigation as a tool for ovulation induction that it should now be considered a safe and effective infertility therapy for office practice. Nevertheless, there remains sufficient mystique about patient selection, optimal dosage and route of delivery, and apprehension on the part of both physicians and patients about cost and inconvenience of medication pumps that gonadotropin-releasing hormone therapy has not enjoyed the widespread acceptance it deserves. This article presents straightforward guidelines for therapy that are based on a detailed review of current literature, together with new information about evolving pump technologic characteristics, that should offer reassurance to the practitioner considering use of gonadotropin-releasing hormone therapy in her/his practice. (AM J OssTET GvNECOL 1988;158:176-85.)

Of the many established and potential therapies for infertility. none has been so widelv or so successfully used as medical induction of ovulation. A prompt m·u­latory response, particularly when pregnancv ensues, makes the use of agents such as clomiphene citrate and bromocriptine as emotionally satisfying for the physi­cian as thev are rewarding for the patient. Nevertheless, there remain a substantial number of anovulatory women who, failing to respond to these conventional office treatments, must travel significant distances to receive more tedious and costlv therapies. The com­plexities of alternate treatments, such as human meno­pausal gonadotropins and gonadotropin-releasing hor­mone (GnRH), and the requisite surveillance have, for the most part, restricted the use of these methods to larger centers that have the necessarv ultrasound and laboratory backup. Better understanding of the neu­roendocrine regulation of the hypothalamic-pituitarv­ovarian axis, the increasing availability of office ultra­sound, and recent developments in infusion pump technology are resulting in daily refinements to the technique of GnRH induction of ovulation that may

From the Division of Reproductive Endocri110/og-y. Department of Obstetrics a11d Gynaerology, Queen's University.

Supported in part ll)· a grant from Physician<' Sen1ire.1 lncmpornted and the Mediral Research Council of Canada.

Presented at the Regional Postgraduate Course of the American Fn­tility Society, Vancouver, British Columbia, Canada, July 16-18, 1987.

Reprint requesl1: Robert L. Reid, MD, Division of Refnoduc­tive Endocrinolog)', Department of Obstetrics and Gpwecology, Queen's Univenil)', Etherington Hall, King.1to11, 011tario, Canada K7L 3N6.

176

soon bring this tool within the grasp of the practicing obstetrician-gynecologist. In this review the theoretical foundations on which GnRH therapy is based will be reviewed. Both the conventional and the controversial indications for its use will be discussed. Finally, it is hoped that, with these simple, practical guidelines for therapy with GnRH, this new treatment modality may be sufficiently demystified to allow its use by the prac­ticing obstetrician-gynecologist.

Theoretical basis of GnRH treatment

The pulsatile pattern of gonadotropin secretion that characterizes the normal menstrual cycle' is now thought to be the result of intermittent delivery of hy­pothalamic GnRH to the pituitary.,.·,

In the normal menstrual cycle it is felt that a variety of neurotransmitters, including endogenous opiates and catecholamines, regulates the pulsatile release of GnRH from the hypothalamus."'' In the absence of pro­nounced physical, psychological, or nutritional stresses that may disrupt GnRH synthesis and secretion, this decapeptide is released as discreet pulses into the hypophyseal-portal venous system and is delivered to the anterior pituitary where it bathes the cells respon­sible for gonadotropin secretion (Fig. I). Coincident with the arrival of the GnRH pulse at the pituitary, luteinizing hormone and follicle-stimulating hormone are released from the gonadotropes and travel through the peripheral circulation to the ovary. Several factors, including the amplitude and frequency of GnRH pulses, 10 the influence of steroidal and nonsteroidal feedback signals to the pituitary, and the differing half-

Volume 158 !'\umber I

GnRH ovulation induction 177

CNS INFLUENCE

Physical l Psychological Stresses N utritionol

Steroidal and Nonsteroidol Feed bock

Fig. I. In the absence of significant pll\sical. pS\d10logical. and nutritional stress. pulsatile release of (;nRH frolll the hvpothalalllus initiates pituitan gonadotropin stimulation of follicular den·l­opment. C.\'S. Central ncrnnis s\stelll: I.II. luteinizing hormone: FSll. follicle-stimulating horlllone. (Reproduced h~ perlllission frolll Reid RL. \"an \'t1gt IH. '.\euroendocrine cn·nts that regulate the lllenstrual nde. Contelllp Oh/C,11 ElHi:'.IO: 1-!i-~l.)

lives of luteinizing hormone (20 minutes) and follicle­stimulating hormone (3 hours), are thought to inHu­ence the relative concentrations of these two gonad­otropins in circulation. I nitiallv follicle-stimulating hormone action is needed for the process of recruit­ment of primary oocnes for the coming reproductiYe cycle." '" Estradiol, which shows a linear increase in circulation as ovarian follicular de\·elopment proceeds. feeds back in concert with other nonsteroidal products from the developing follicle to inhibit the release of follicle-stimulating hormone and augment luteinizing hormone secretion through actions at hvpothalamic and pituitarv sites. This intricate feedback mechanism results (in most circumstances) in the maturation of a single follicle and thus prevents multiple o\'ulation, an extremely uncommon event in the normal human re­productive cycle (Fig. 2).' 1

Experiments in the rhesus monkey made deficient in GnRH by production of a lesion in the arcuate nucleus have demonstrated that intermittent pulsatile deliven· of GnRH at a fixed rate (one pulse per hour) is suffi­cient to initiate a normal sequence of pubertal events culminating in full ovulatorv function. 1 ' Although both amplitude and frequency ofluteinizing hormone pulses are known to vary at di(ferent stages of the menstrual cycle,'-·, it appears that therapy with GnRH need not achieve this same level of precision. Fixed dosages of

GnRH delivered in pulses at constallt time intervals ranging from 1 to 2 hours are sufficient to maintain normal ovulatory and corpus luteal function in re­peated cvcles.' 1

GnRH treatment, in theorv, when properly admin­istered, should lead to increased release of pituitarv gonadotropins without influencing the negati\·e feed­back system between the developing m·arian follicles and the pituitarv. As a result. innate mechanisms for regulating the number of follicles recruited should re­main intact, and thereby the complications associated with multiple ondation Gtll be avoided (Fig. 2). In prac­tice, it has been obsen·ed that large doses of CnRH mav, in fact, override innate control mechanisms and lead to multiple o\·ulation ... "; hence dosage per pulse is a second critical determinant of successful CnRH therapy. Clinical experience indicates that when dos­ages are properly selected the infrequency of multiple ovulation obviates the need that exists with other forms of gonadotropin therapy to monitor follicle numbers rigorously.

Patient assessment

A thorough assessment of the anondatorv woman ts essential before the initiation of any therapy. One of the most common causes for unsuccessful medical in­duction of ovulation is erroneous patient classification

178 Reid, Fretts, and Van Vugt

NORMAL

FSH LH,, /,-"'-..ill. I/

@ MENOPAUSAL

GONADOTROPINS

-ve

CLOMIPHENE

[ID

GnRH

Fig. 2. Schematic diagram comparing hypothalamic-pituitary

ovarian interrelationships with different forms of ovulation. A, Estrogen from the developing follicle normally inhibits fur­

ther pituitary follicle-stimulating hormone release. B, Clomi­phene citrate blocks the feedback inhibition of estrogen, which

results in augmentation of pituitary follicle-stimulating hor­

mone release. E,, Estradiol. C, Menopausal gonadotropins by­pass all endogenous regulatory mechanisms and thus carry

greater risk for multiple pregnancy. D, Exogenous GnRH elic­its pituitary gonadotropin release, yet negative feedback ef­

fects on the pituitary remain intact, thus reducing the risk of ovarian hyperstimulation.

resulting in the selection of an inappropriate treatment

modality. In many circumstances history and physical

examination alone are sufficient to lend a high index

of assurance to the diagnosis of the nature of the ovu­

latory disorder. In the amenorrheic woman a history of recent weight

loss or of other significant physical, psychological, or

nutritional stresses should focus attention on the pos­

sibility of suppressed hypothalamic GnRH secretion as

the underlying pathophysiologic mechanism.'" Evi­

dence of anosmia or of a midline facial defect in a

woman with primary amenorrhea should suggest a con­genital absence of GnRH production.,,,_,,

In contrast, acne, hirsutism, and oligomenorrhea,

particularly if associated with recent weight gain or

long-standing obesity, point toward a pattern of chronic

anovulation associated with polycystic ovary disease.''

January 1988 Am J Obstet Gynecol

Table I. Indications for GnRH induction

of ovulation

A. Established Complete or partial deficiency of

endogenous GnRH Congenital

Isolated GnRH deficiency Associated with anosmia (female

Kallman's syndrome) Associated with midline facial

defects Acquired

Organic disease of hypothalamus or pituitary stalk

Postsurgical/traumatic hypothalamic or pituitary stalk damage

Stress-induced (hypothalamic) amenorrhea* Exercise-induced Nutritional deprivation Psychological stress

B. Experimental: Polycystic ovary disease H yperprolactinemia Luteal phase defects Cervical mucus deficiency Induction of multiple ovulation for

in vitro fertilization

*GnRH therapy under these circumstances should be un­dertaken only after the primary process has been stabilized through life-style modification.

Hyperandrogenism with polycystic ovary disease in the

nonobese individual is often associated with insulin re­

sistance."' The presence of galactorrhea and/or amenorrhea

should suggest the likelihood of hyperprolactinemia

while hot flushes and inadequate vaginal lubrication

would point toward amenorrhea on the basis of ovarian

failure. Finally, clues to the presence of other subtle

systemic diseases, such as thyroid or adrenal dysfunc­

tion, should be sought. A few simple endocrine tests are generally sufficient

to confirm the diagnostic impression and to determine

the need for, and appropriateness of, medication for

ovulation induction. Minimum requirements in the pa­

tient who has amenorrhea should include a determi­

nation of luteinizing hormone, follicle-stimulating hor­

mone, and prolactin levels and thyroid function tests.

Additional testing may be indicated by the clinical pre­

sentation. An abnormality of at least one serum androgen level

(free or total testosterone and/or dehydroepiandroste­

rone sulfate) exists in most patients with hirsutism.'·1

The degree of hyperandrogenism is often correlated

with the level of resistance to ovulation induction.

Selection of patients for GnRH therapy

Established indications for GnRH therapy. Wo­

men with congenital GnRH deficiency, those with

acquired GnRH deficiencies resulting from organic

Volume 158 Number I

hypothalamic-pituitary disease, and those with suppres­sion of GnRH release as a result of physical, psycho­logical, or nutritional stresses often have extremely low circulating gonadotropin levels and clinical features of hypoestrogenism. '" In circumstances where pubertal development has been delayed because of complete or partial congenital deficiency ofGnRH, appropriate ste­roid hormone replacement is first indicated to complete the pubertal transition. Similarly, when acquired GnRH deficiency has resulted in prolonged hypoestrogenism, endometrial priming with cyclic estrogen and progestin for several cycles before GnRH therapy is probably warranted. As anticipated, exogenous GnRH admin­istered in an appropriate dosage and pulse frequency in each of these circumstances has been shown to promptly restore full ovulatory function and ferti­lity."'·,.,_,, It is appropriate, however, in cases involving acquired GnRH deficiency to direct initial therapeutic efforts toward correction of the underlying problems or aberrant life-style patterns that were responsible for the amenorrhea in the first place. Even with correction of these underlying problems the amenorrhea may per­sist, and it is at this juncture that GnRH therapy for ovulation induction may be appropriate. Indications for GnRH therapy are listed in Table I.

Experimental uses of GnRH therapy Polycystic ovary syndrome. The most common pattern

of chronic anovulation is that associated with polycystic ovary disease. Elevated luteinizing hormone/follicle­stimulating hormone ratios in this disorder suggest the possibility of excessive hypothalamic GnRH secretion and/or increased pituitary sensitivity to GnRH occa­sioned by tonic elevation in circulating estrogen con­centrations."" In vitro'" "" and in vivo" "" studies have confirmed that supplementation with follicle­stimulating hormone alone is sufficient to correct the ovarian dysfunction in this disorder and to restore a normal pattern of ovulation. Menopausal gonadotro­pins and purified follicle-stimulating hormone," al­though highly effective for ovulation induction in this setting, have the drawback that they bypass endogenous mechanisms governing the number of recruited folli­cles and therefore require judicious administration and rigorous monitoring to avoid multiple pregnancy (Fig. 2). Clomiphene citrate, which functions as a very weak estrogen, occupies the estrogen receptors of the hypothalamus and pituitary and thereby blocks the follicle-stimulating hormone inhibiting property of cir­culating estrogen."" As a result, there is a rise in cir­culating concentrations of follicle-stimulating hormone and resumption of follicular maturation. Blockade of the negative feedback signal of estradiol carries with it the attendant risk of follicle-stimulating hormone oversecretion with the result that the number of mature follicles occasionally exceeds the normal ovulatory quo­tient for man (Fig. 2). The risk of multiple pregnancy

GnRH ovulation induction 179

in women treated with clomiphene citrate is reported to approximate 8% but may, in practice, be lower."' The antiestrogenic property of clomiphene citrate may also have the unwanted effect of impairing cervical mucus production.

In theory GnRH therapy should not benefit the woman with polycystic ovary syndrome. The abnor­mally elevated luteinizing hormone/follicle-stimulating hormone ratio in this disorder has been attributed in part to the exaggerated pulsatile release of GnRH by the hypothalamus and increased pituitary sensitivity to pulses of GnRH.n "' It is known that excesses in either amplitude or frequency of GnRH pulses will lead to an increase in the luteinizing hormone/follicle-stimulating hormone ratio10

; hence the addition of exogenous GnRH pulses when endogenous activity is alreadv in­creased, in theory, should do nothing to improve the unfavorable gonadotropin profile unless the exogenous program overrides the natural one."" In practice, results have been mixed, with some investigators reporting poor rates of ovulation""·'17 and others indicating better success with both subcutaneous"" and intravenous"' "' routes. Nevertheless, pregnancy rates in patients with polycystic ovary disease have been considerably lower than those reported for other patients receiving GnRH therapy."''"' which raises doubts about the utility of this approach, particularly since treatment in these circum­stances may require much larger doses of GnRH and more prolonged periods of treatment.

Hyperprolactinemia. Another condition in which GnRH is found to restore fertility is anovulation sec­ondary to hyperprolactinemia."0 11

· '" However, except in circumstances where allergy or adverse reaction to prolactin-suppressing medications precludes their use, it would seem more appropriate, after careful evalua­tion, to restore the euprolactinemic state by use of bro­mocriptine and thus allow resumption of spontaneous ovulatory cycles.

Luteal phase defects and cervical mucus deficienc_v. Iso­lated reports about the use of GnRH therapy for cor­rection of infertility caused by luteal phase defects" 11

or cervical mucus deficiency'' have appeared but since other simpler means exist to correct these problems the use of GnRH to treat these disorders must still be con­sidered experimental.

Induction of multiple ovulation for in vitro fntiliwtion. Liu et al.'" have demonstrated the potential for the use of large intravenous dosages of GnRH in normal women to induce multiple follicular development for in vitro fertilization. Using dosages of 10 µg intrave­nously every hour these investigators induced two to five dominant follicles in all su~jects tested. In con­tradistinction to the situation in which multiple follicles are induced with menopausal gonadotropins, subjects consistently showed spontaneous luteinizing hormone surges without the need for exogenous human chori-

180 Reid, Fretts, and Van Vugt

1000

900

800

E ....... 700 Cl ci

600 J: a::: 500 c: (.!)

400

300

200

100

S.C. 1.V. S.C. l.V.

2.,og GnRH 20)Jg GnRH

Fig. 3. Peak plasma GnRll concentrations achic\'ed after low

(2 µg) and high (20 µg) doses of (;nRH by the subcutaneous

(S.C.) and intravenous (I. V.) routes. (Modified bv permission

from Loucopoulos A, Ferin ~I. Vande Wiele RL. et al. Pulsatile

administration of gonadotropin-releasing hormone for in­

duction of ovulation. A~t .J O!lSTET Gv:-;u:o1. 1984; 148:895.)

omc gonadotropin. To date, no comparative studies

have been undertaken to compare this technique with

conventional ovarian stimulating protocols involving

clomiphene citrate and menopausal gonadotropins.

Resistant m•ary syndrome. Women with amenorrhea re­

sulting from ovarian failure with premature depletion

of oocytes would not be expected to respond to exog­

enous GnRH. To date no one has attempted to use

GnRH therapv in women with ovarian failure on the

basis of the so-called "resistant ovary" syndrome. In this

situation the ovary contains primordial follicles but fails

to respond to endogenous gonadotropins for a varietv

of postulated reasons, including production of abnor­

mal gonadotropins, antibodies to gonadotropin recep­

tors, or postreceptor defects.•·· In theory it would seem

unlikely that GnRH therapy would be successful in this

situation.

Mode of delivery and outcome

Currently there are only two feasible routes of ad­

ministration available for GnRH therapy: subcutaneous

and intravenous. Although the efficacv of intranasal

GnRH has been demonstrated in a preliminary way,"'

the wide-scale application of this mode of delivery will

undoubtedly have to await techniques for improving

intranasal absorption (present absorption rate of <4'/f)

or a reduction in the price of synthetic GnRH. Ex-

.January 1988 Am .J Obstel Gvnecol

tremely potent analogues of GnRH reach effective con­

centrations by the intranasal route; however, because

of their long durations of action it is impossible to

achieve the pulsatile delivery that is needed for ovu­

lation induction."

The issues of efficacy, safety, and patient acceptability

of subcutaneous and intravenous administration are

gradually being resolved. Clear differences in drug

availability by these two routes of delivery"" :n. '" prob­

ably account for many of the reported differences in

response rates. Peak GnRH concentrations after intra­

venous delivery are three to five times greater than after

subcutaneous injection (Fig. 3). Insufficient dosage

had been suggested<''- -,o as one factor contributing to

the disappointing or inconsistent results of subcutane­

cms GnRH therapy reported by several investiga­

tors"'· 1:1. -,, ··"; however, the findings that some patients

respond promptly to small subcutaneous doses 1" -,,,_ ··"--.

1

and that others who fail to respond to high subcuta­

neous doses during prolonged treatment courses may respond promptly to intravenous therapy"' :i-.. '"· -,,_ -,-, -,,;

suggest that other factors must be involved. Whether

factors such as site of subcutaneous injection, degree

of physical activity of subjects, presence or absence of

obesity, frequency of changing injection site, or rate of

infusion add further variation to drug availability after

subcutaneous administration is unknown, but these

considerations might explain why some patients who

fail to respond to subcutaneous therapy respond

promptly to intravenous GnRH administration. In ad­

dition, subcutaneous delivery is more often associated

with prolongation of the follicular phase-,,-,, and a luteal

phase defect.-"' -," .,, -,, Since both the pulse dosage and

duration of therapy are reduced with intravenous ad­

ministration, substantial cost savings may result when

the intravenous route is used. Rates of ovulation (90%

to 95'7c) and pregnancy (30'/f to 35% of all treatment

cycles) from published data are comparable with those

of intravenous and subcutaneous therapy; however, it

must be remembered that some of these successes with

intravenous therapv were previously failures with sub­cutaneous t reatmen t.-.x.,;o

The simplicity of subcutaneous therapy from the

standpoint of both physician and patient probably war­

rants an initial attempt by this route. Patients rank sub­

cutaneous delivery of GnRH more satisfactory in terms

of comfort and simplicity but will soon become frus­

trated by the cost and time delays if a satisfactory ovu­

latory response is not achieved during the first cycle of

subcutaneous treatment.-'" Accordingly, if subcuta­

neous therapy is chosen and dosages of 20 to 40 µg

every 2 hours do not achieve an adequate follicular

response by 30 days, the patient should be switched to

intravenous therapy.-.'

Most studies have reported comparable success

Volume 158 !\umber I

GnRH ovulation induction 181

40:::: E

30 ......

"' 20.:

10 ~ F""=-""""-"~~~~--~~'-----~----=~~~"~~-=1---=-=~~~------10

MAY JUNE JULY AUGUST SEPT

Fig. 4. Repetitive cycles of intravenous GnRH therapy (2.5 µg every 1.5 hours) with luteal phase support of human chorionic gonadotropin (ltCG) injections (2500 JU every 3 days). In the July treatment cycle GnRH was discontinued because of improper interpretation of an ultrasound scan that led to the mistaken impression that ovulation had occurred. Pregnancy resulted in treatment cycle No. 4. Po, Progesterone. (Reproduced by permission from Reid RL, Sauerbrei E. Evaluation of techniques for induction of ovulation in outpatients employing pulsatile gonadotropin-releasing hormone. A\I j 0BSTET GY:\ECO!. 1984; 148:648.)

with pulse frequencies ranging from 60 to 120 min­utes.'"·.,, "1. "' Daytime self-administration has been suc­cessfully used by three groups.··'"' '" While selected for its simplicity, this route of administration (with larger GnRH pulses given on retiring and on rising) may. in fact, more closelv mimic endogenous GnRH release. Soules et al.'··· have recently observed a reduced fre­quency of high-amplitude luteinizing hormone pulses overnight in normal women. Currently 2.5 to 5 µg per dose is recommended as the starting dose for intra­venous therapy while a dosage of 5 to 20 µg is usually chosen to initiate subcutaneous therapy. Dosage ad­justments outside this range may be necessary in dif­ferent clinical and experimental settings.

Management of the luteal phase

At the present, the weight of evidence suggests that continued hormonal support is necessarv for normal functioning of the corpus luteum in the human. Asch et al."'; presented evidence that abolition of endogenous luteinizing hormone in rhesus monkeys by hypophy­sectomy immediately after ovulation had no adverse effect on corpus luteal function. This finding was in contrast to the work of Hutchison and Zeleznik,';' who found that failure of the corpus luteum resulted im­mediately if there was interruption of exogenous GnRH support in GnRH-deficient rhesus monkevs. In humans there is abundant evidence that continuing support of the corpus luteum is required in most GnRH-induced cycles. Anecdotal reports of premature menstruation associated with pump failure";·,;, have been supported by the observation that luteal phase duration is significantly ·shortened in the absence of luteal phase human chorionic gonadotropin injec­tions.m Hanker et al.rn have suggested that the luteal

phase defects that follow GnRH induction of ontlation may be the result of inadequate preparation of the corpus luteum during the follicular phase. Comparing standard pulsatile GnRH therapy (even· 96 minutes) to a frequency-varied regimen (every 4 hours for 2 days, every 3 hours for I day, then every 9(i minutes) they observed that the luteal insufficiency common to

the first group was not apparent in the latter group. They suggested that the initial slow pulse frequencv may result in greater follicle-stimulating hormone release'" similar to that occurring immediately before menstruation in the normal menstrual cycle."' Greater follicle-stimulating hormone exposure at that time mav, in turn, induce changes in the developing follicle (in­duction of luteinizing hormone receptors) that favor more normal corpus luteal function later on. While these intriguing observations must be considered pre­liminary, they warrant further study since thev might help to resolve the apparently discrepanr findings about the need for corpus luteal support reporred bv Asch et al.6

"

At the present, luteal support is recommended for all patients on a regimen of GnRH therapy. This has been accomplished by merely maintaining pulsatile de­livery of GnRH" .,, " (which avoids the need for de­tecting the time of ovulation), by switching to inter­mittent human chorionic gonadotropin injections."'' " or by giving daily progesterone suppositories'' after ovulation. Although GnRH by nasal spray (200 µg every 4 hours) has been tried, it appears to be ineffec­tive in providing the necessary corpus luteal support."' If a satisfactory technique is used to detect ovulation," then it is probably simpler, safer, and more satisfactory to patients to discontinue the GnRH pump about 48 hours after ovulation in favor of human chorionic go-

182 Reid, Fretts, and Van Vugt

nadotropin injections (2500 U every 3 days for four times)52 (Fig. 4).

Current pump technology

A variety of diferent automated pumps have been developed to allow around-the-dock administration. The pumps vary in size and price but are generally small enough to be worn on the body with a small cannula placed either intravenously or subcutaneously. Pumps presently available in North America include the Auto-Syringe pump52 (Auto Syringe Inc., Hookset, NH 03 I 04), the slightly more compact Pulsamat (Fer­ring Laboratories, Inc., Suffern, NY 10901),75 and a much smaller, manually driven penpump52 (Markwell Medical Institute Inc., Box 573, Racine, Wis.). Each of these systems has the advantage that the continuity of the drug's delivery system need be broken only every 2 to 3 days to refill the syringe. Self-administration of GnRH has been performed with an indwelling heparin lock6

'· 64

; however, this system has the disadvantage of more frequent breaks in the continuity and hence a theoretical and perhaps practical4° increase in the risk of infection.

A newly patented pump (Timpulse) was developed at Queen's University for the purpose of delivering GnRH. Disposable medication cassettes charged by a leaf spring mechanism deliver GnRH in the desired concentration over a period ranging from IO to 20 days without the need to refill. The leaf spring design avoids the need for cumbersome gearboxes and large batter­ies, both of which add considerably to the size and cost of other pumps.

As pumps become smaller and easier to load with medication, we are likely to see greater acceptance of this form of treatment by patients and broader appli­cation of this technique by gynaecologists in practice.

Practical application of GnRH therapy

Just before the initiation of GnRH therapy an ultra­sonogram should be obtained to assess the pretreat­ment status of the endometrium and ovaries. Some conditions, such as endometriosis, can, on ultrasound, be confused with a developing follicle; hence, a baseline scan is valuable.

In most cases the serial blood tests used by research­ers to assess the various modes of GnRH therapy are not generally required in a clinical setting; how­ever, baseline determinations of luteinizing hormone, follicle-stimulating hormone, prolactin, and estradiol are worthwhile before treatment is initiated.

Education of patients about the purpose of therapy, how to charge or refill the pump, and signs or symp­toms of local or systemic infection is vital to the success and safety of outpatient GnRH therapy. Patients may choose the pump that best suits their life-style and pock-

January 1988 Am J Obstet Gynecol

etbook. Minor irritation at the injection site can be ex­pected and is normal; however, patients should be told to report promptly any signs of local or systemic in­fection. Spreading erythema, chills or fever, and mod­erate to severe pain at the injection site are all signs that require immediate medical attention and should be described to the patient.

Patients are initially started on subcutaneous GnRH therapy at a dosage of 5 µg every 2 hours. The first follow-up visit should be scheduled for 1 week after the initiation of therapy. Pelvic examination is con­ducted to determine whether estrogenic changes are developing in cervical mucus. If these changes are ev­ident, ultrasound examination is scheduled to docu­ment the number and size of developing follicles. There is a close correlation between follicular diameter and peripheral plasma estradiol levels.76 Although 15 mm follicles may, on occasion, rupture, indicating ovulation, such follicles usually grow by 2 to 3 mm/day and reach diameters of 20 to 25 mm before ovulation occurs. As a rough "rule of thumb," ovulation can be expected to occur approximately 3 to 5 days after the follicle has reached 15 mm in diameter.74

• n When the follicle ap­proaches 18 to 20 mm we advise patients to have in­tercourse daily. Monoclonal antibody kits may be used to identify the luteinizing hormone surge, thus helping the patient to pinpoint the most likely time of ovulation.

If patients have shown no evidence of response by I 0 days with subcutaneous therapy, the dosage is in­creased to 20 µg per pulse for a further IO days. If the patient still has shown no evidence of response by 20 days the dosage may be increased by 10 µg every 5 days until day 30; if no response is observed at this dosage, intravenous therapy should be initiated.

Intravenous therapy is conducted by use of the basilic vein of the forearm with a long connecting tubing to the pump that is worn in a brassiere or about the waist, depending on the model selected. A dosage of 2.5 to 5 µg (approximating 75 to 100 ng/kg) every 90 minutes is used initially with increments every IO days as indi­cated by clinical response. The average time from ini­tiation of treatment to ovulation ranges from IO to 20 days for intravenous infusion but may be as long as 15 to 30 days with subcutaneous treatment. In contra­distinction to the situation in patients undergoing ther­apy with menopausal gonadotropins, in which case a spontaneous luteinizing hormone surge occurs infre­quently, the experience with GnRH therapy indicates that a spontaneous luteinizing hormone surge is the norm for this treatment.

Basal body temperature shift will provide presump­tive evidence of ovulation that can be confirmed by a follow-up ultrasound scan or serum progesterone de­termination. Depending on which program of luteal phase support has been chosen, the pump is either

Volume 158 Number I

continued in the usual fashion or discontinued in favor of intermittent human chorionic gonadotropin injec­tions. The luteal phase is typically prolonged to 16 days when hCG is given every 3 days for four doses.52

Complications of GnRH therapy

The complications of ovulation induction with GnRH have been relatively few and most are rapidly amenable to therapeutic interventions. Although subcutaneous delivery is theoretically the least likely to lead to prob­lems of bleeding, embolism, or infection, there have been several instances where hematomas have devel­oped at the sites of subcutaneous needle or catheter insertion.68 Since heparin is not necessary for delivery of GnRH at subcutaneous sites and it may promote hematoma formation, it is not used as an additive in the GnRH solution when this route of delivery is se­lected. Local inflammation at the site of subcutaneous needle insertion has also been encountered" although this problem is usually avoided by attention to proper sterile technique. There have been reports of subcu­taneous abscess formation requiring drainage'6· 55 and we have seen one patient who developed local inflam­mation with bilateral inguinal adenopathy (Reid RL, unpublished data).

With intravenous therapy the break in the continuity of the tubing used to deliver GnRH from the pump to the vein will result in back bleeding and such problems have been encountered sporadically.52 Although air em­bolus has been considered a potential complication, in practice this has never been a problem. Superficial phle­bitis has been reported on several occasions"· 52 and the use of repeated injections to an intravenous heparin lock was, on one occasion, associated with systemic sep­sis.•0 Our experience has indicated that, with appro­priate sterile precautions, a small-gauge Teflon cathe­ter, when appropriately anchored into the basilic vein of the forearm and covered with a waterproof dressing, will often be tolerated for periods long enough to pro­duce ovulation without the need for changing the site of catheter insertion.52

There have been reports of formation of antibodies to exogenous GnRH in patients born with a congenital deficiency of GnRH1

"· 79 and more recent documenta­

tion of such antibody formation even in individuals who have had, or who currently have, some degree of en­dogenous GnRH production."0· 81 Both urticaria79 and an overt anaphylactic reaction"' have been reported in isolated cases after repeated treatment cycles with ex­ogenous GnRH. In practice this problem is unusual since most patients on a regimen of GnRH therapy respond in successive cycles to the same dosage of GnRH. Only if resista~ce to high dosages of GnRH becomes apparent in an individual who formerly re­sponded to GnRH or in the presence of obvious allergic

GnRH ovulation induction 183

manifestations when GnRH is restarted should a search for anti-GnRH antibodies be conducted. In this cir­cumstance, conventional stimulation protocols with menopausal gonadotropins provide an effective alter­native.

Although theoretically the intact negative feedback mechanisms that are maintained during GnRH therapy should prevent multiple follicular development, there is clear evidence that ovarian hyperstimulation may oc­cur on some occasions. For the most part, these episodes have been associated with large intravenous dosages of GnRH. Ovarian hyperstimulation has been docu­mented by ultrasound evidence of multiple follicular development although the patients were without clin­ical signs or symptoms and the multiple follicles re­gressed after GnRH therapy was discontinued.68

· "0 In

one case, after developing a single follicle in two suc­cessive months with GnRH therapy, the patient went on to develop multiple follicles in the third month while being maintained on a regimen of the same GnRH dosage.55 The incidence of multiple pregnancies re­sulting with GnRH therapy is estimated to be approx­imately 7%,60 with most of these being twins""· 70 but with occasional reports of triplets surfacing."·"·" Ma­son et al." have suggested that the use of human cho­rionic gonadotropin to trigger ovulation may incite other secondary follicles to ovulate and have since aban­doned this procedure.

The rate of spontaneous abortion with GnRH ther­apy to date has been approximately 20%, which com­pares favorably with the spontaneous abortion rate in the general population. 60

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