GnRH Therapy Research Articles

The hemodynamic effect of GnRH agonist therapy on uterine leiomyoma vascularity: a prospective study using transvaginal color Doppler sonography.

The objective of this study was to correlate, during 12 weeks of therapy with gonadotropin releasing hormone agonist (GnRH-a), the chronological effect and the hemodynamic changes on the uterine artery and the leiomyometrial supplying vessels. Twenty-three premenopausal women with clinically diagnosed uterine leiomyomas received 3.75 mg of leuprolide acetate intramuscularly every 4 weeks for 12 weeks. Pretreatment values of serum estradiol, uterine and leiomyoma volumes and blood flow characteristics of the main uterine artery and leiomyoma supplying vessels-resistance index (RI), pulsatility index (PI) and peak-systolic velocity, obtained by transvaginal color Doppler sonography-were compared with treatment values at 4, 8 and 12 weeks of leuprolide acetate therapy. The first event in the chronological response to the GnRH-a therapy was a statistically significant increase in RI and PI values for major leiomyoma vessels, observed at the end of the 4th week (p < 0.05), which increased significantly after 8 and 12 weeks (p < 0.01 and p < 0.001, respectively). These findings were in direct correlation with a significant decrease of estradiol levels after 4, 8 and 12 weeks (p < 0.05, p < 0.001 and p < 0.001, respectively). The significant decrease of blood flow in the leiomyometrial vessels was followed by a significant decrease of the main uterine artery blood flow after 8 weeks and uterine and leiomyoma volumes by 42% and 55%, respectively, after 12 weeks of GnRH-a therapy. We concluded that a significant increase in leiomyometrial vessels RI and PI values, which was found 4 weeks after the first dose of GnRH-a, but without major leiomyoma volume decrease, emphasizes that the first significant effect of GnRH therapy in the process of uterine and leiomyoma volume shrinkage is the reduction of leiomyometrial rather than uterine blood flow. This effect is followed by a considerable reduction of uterine vascularity and a significant decrease of uterine and leiomyoma volumes. If a decrease of blood loss during myomectomy is the main aim of GnRH-a therapy, we believe that 8 weeks would be an appropriate therapy duration.

Hormonal Therapy of Male Hypogonadism

The goals of hormonal treatment of male hypogonadism depend upon the stage of sexual development in which gonadal failure occurs. Androgen replacement therapy is used to induce and maintain normal secondary sexual characteristics, sexual function, and behavior in prepubertal boys and men with either primary or secondary hypogonadism. Parenteral testosterone esters, testosterone enanthate or cypionate, are the most effective, safe, practical, and inexpensive androgen preparations available for this purpose. They are the treatment of choice for androgen replacement therapy. A recently approved scrotal transdermal testosterone system provides an alternative to testosterone esters in selected patients. In boys or men with secondary hypogonadism, gonadotropin or GnRH therapy may be used instead of testosterone therapy to stimulate endogenous testosterone production. Because of their greater expense and complexity, however, these modalities are usually reserved for men with gonadotropin deficiency who desire fertility and in whom spermatogenesis must be initiated and maintained. Gonadotropin therapy is begun with hCG alone. In men with partial or previously treated gonadotropin deficiency, or in men with postpubertal hypogonadotropic hypogonadism, hCG treatment alone may be sufficient to stimulate spermatogenesis and fertility. In most men with prepubertal hypogonadotropic hypogonadism, however, combined treatment with hCG plus hMG is needed to initiate sperm production and fertility. Pulsatile GnRH therapy may be used to stimulate testosterone production and spermatogenesis in men with secondary hypogonadism who have hypothalamic defects, such as idiopathic hypogonadotropic hypogonadism or Kallmann's syndrome.

Mechanism of anovulation in hyperprolactinemic amenorrhea determined by pulsatile gonadotropin-releasing hormone injection combined with human chorionic gonadotropin

To clarify the mechanism of anovulation in hyperprolactinemic anovulatory women by subcutaneous (SC) pulsatile GnRH injection. Prospective clinical study. Studies were made on at the Department of Obstetrics and Gynecology, the University of Tokushima, School of Medicine. Six hyperprolactinemic (group 1) and 7 normoprolactinemic (group 2) anovulatory patients were studied. After examinations of pulsatile secretion of LH, the GnRH test, thyrotropin-releasing hormone test and estrogen test, pulsatile GnRH treatment (20 micrograms/2 hours SC) was performed. Two protocols were tested on each patient. In the non-hCG protocol, GnRH treatment was continued until ovulation. In the hCG protocol, 5,000 IU of hCG was injected to induce ovulation when follicles were fully mature. The rates of follicular maturation and ovulation, serum E2 and P in the two groups. Pulsatile LH secretion was impaired in both groups. LH release 48 hours after estrogen injection was impaired in group 1 but not in group 2. Follicles matured on pulsatile GnRH treatment in all cycles in both groups. However, with the non-hCG protocol, ovulation occurred in only 17% of group 1, but in 89% of group 2. With the hCG protocol ovulation occurred in all cycles in both groups. The main cause of anovulation is impaired gonadotropin pulsatility and derangement of the estrogen-positive feedback effect on LH secretion in hyperprolactinemic patients, their ovarian response to gonadotropin being well maintained. Subcutaneous pulsatile GnRH therapy combined with hCG can be used as an alternative to bromocriptine treatment for induction of ovulation in these patients.

Ovulation and the Polycystic Ovary Syndrome

In the 1930s, Stein and Leventhal added amenorrhoea to anovulatory dysfunctional uterine bleeding among the known clinical manifestations of the polycystic ovary syndrome (PCOS). Whatever the menstrual pattern, infrequent or absent ovulation with symmetrical enlargement of the ovaries is now a familiar abnormality in women of reproductive age. Diagnosis of PCOS has developed from just the clinically obvious to an appreciation, through ultrasound imaging of the ovaries and endocrine testing, of its subtler forms. Today's clinicians will identify PCOS on the ultrasound image of many small follicles apparent in the periphery of both ovaries, on raised serum unbound testosterone assays, on exaggeration of serum LH levels with the start of pulsatile GnRH therapy, and on follicular overresponsiveness to injections of FSH. Once among the most treatable causes of infertility, ovulation-induction for PCOS remained unsophisticated while microsurgery and assisted conception dissolved frontiers for other causes of infertility. Whereas we now have the benefit of high technology embryo cryostorage to cope with embarrassingly high yields of PCOS oocytes, we still need to explain why, the bigger the ovaries, the more likely (we have long known it to be) that PCOS can be cured simply by reducing ovarian mass. Some cases of PCOS are hereditary and most seem constitutionally determined. PCOS is so common that the questions must be asked, Are we appreciating an extreme of normal? Could the milder forms of PCOS have--or could PCOS have had--evolutionary usefulness?

Preservation of fertility despite subnormal gonadotropin and testosterone levels after cessation of pulsatile gonadotropin-releasing hormone therapy in a man with Kallmann’s syndrome

A man with IHH and anosmia presented in 1980. He was successfully treated with various hormonal regimens; four children were conceived with hCG or pulsatile GnRH therapy. The patient discontinued GnRH after the fourth child was conceived, and testosterone enanthate injections were prescribed. However, he took the injections only briefly and 15 months later he demonstrated continuing spermatogenesis despite low serum FSH and LH levels. His wife successfully became pregnant. This case adds to the recognized range of recovery in IHH, with fertility despite stopping hormonal therapy and despite low serum gonadotropin and T levels.

Alternate‐day GnRH therapy for ovarian hypofunction induced by weight loss: treatment of six patients who remained amenorrhoeic after weight gain

Body weight loss has an adverse effect on the pituitary-ovarian function, and no restoration of the function occurs in 20-30% of patients even after the recovery of body weight. In the present study, the efficacy of alternate-day GnRH therapy was investigated in six patients whose pituitary-ovarian function had not recovered at 15 months to 6 years after the recovery of body weight. Synthetic GnRH (100 micrograms) was injected intramuscularly on alternate days for a total of 12 doses. On the completion of GnRH administration the efficacy of clomiphene-human chorionic gonadotrophin (hCG) therapy was evaluated. A GnRH loading test and evaluation of LH secretion patterns were also performed to investigate the changes in hypothalamic-pituitary-ovarian function secondary to GnRH treatment. All six patients ovulated in response to clomiphene-hCG therapy after 1-3 courses of GnRH treatment. The ovulatory response to clomiphene-hCG continued during follow-up periods of 5 months to 5 years. The initial hormonal change induced by GnRH treatment was a rise in the basal serum FSH level and a return of the FSH response to GnRH loading. This was followed by an increase in serum LH and the return of LH response to GnRH loading. In all six patients, pulsatile LH secretion was absent before starting GnRH treatment. GnRH treatment produced LH pulses in five of the six patients, although the pulse frequency was less than that in normally cycling women. A further increase in the pulse frequency was observed during clomiphene therapy. Alternate-day GnRH administration is effective in inducing responsiveness to clomiphene in patients with anovulation secondary to weight loss.

GnRH agonist analogs and hysteroscopic resection of myomas

OBJECTIVES: The purpose of this study was to evaluate the effects of pretreatment with GnRH analogs and hysteroscopic resection of submucous myomas previously deemed to be contraindicated for this approach. METHODS: Twenty-five patients were included in this study. Patients were assessed by ultrasonography and diagnostic hysteroscopy. They were treated with depot GnRH analogs for 3 months and then scheduled for hysteroscopic surgery. RESULTS: After GnRH therapy the diameter was 61 ± 10% of the initial diameter. In one patient, therapy was almost ineffective. Hysteroscopic surgery was possible in all 25 patients. Seven patients presented an intramural myoma that was not possible to remove entirely during the first attempt. After dessication and 2 supplementary months of GnRH analog therapy, a second surgical attempt was successful in complete removal of the tumor in all except one case. In one patient hysterectomy 15 days after hysteroscopic surgery was necessary for incoercible bleeding due to a deep adenomiosis. CONCLUSIONS: A combined medical and surgical approach seems to reduce the limit of hysteroscopic surgery and avoid open myomectomy or hysterectomy in a well selected group of patients.

Pulsatile Gonadotropin- Releasing Hormone Therapy for Ovulatory Disorders

Pulsatile GnRH remains a physiologic method of inducing ovulation that is effective and safer than other parenteral preparations. Its lower rate of acceptance in the United States stands in curious contrast to its widespread usage in other countries as a second-line (postclomiphene) technique of choice for ovulation induction. In a high-technology era such as ours, women who may benefit from pulsatile GnRH therapy should not be forgotten. By far the most favorable results are obtained in women with primary or secondary hypothalamic amenorrhea. In such women, pregnancy rates appear comparable to those achieved with exogenous gonadotropins with a much lower risk of multiple pregnancy and ovarian hyperstimulation. These positive aspects, combined with the decreased need for clinical monitoring and the increased sense of control imparted to the patient, lead to the conclusion that women with uncomplicated hypothalamic-pituitary disorders are the ideal patient group to consider for therapy. The application of pulsatile GnRH therapy to other groups of women relies on limited data. By all means, women with polycystic ovarian syndrome who have not ovulated or conceived after other forms of treatment should be considered because reasonable pregnancy salvage can be obtained. We have noted a first-cycle successful pregnancy after failure of exogenous gonadotropins, with or without a superimposed GnRH agonist, and even in vitro fertilization with multiple embryo transfers. Before such invasive, high-technology procedures are entertained, it would appear prudent to consider this simple alternative in women with an overactive hypothalamic-pituitary axis, as seen in polycystic ovarian syndrome. Other ovulatory defects also may be amenable to treatment with pulsatile GnRH, but their practical usefulness will await further clinical study.

GnRH therapy in stallions

GnRH therapy in stallions

Non-responsiveness of serum gonadotropins and testosterone to pulsatile GnRH in hemochromatosis suggesting a pituitary defect.

We investigated the potential pituitary origin of gonadal insufficiency in hemochromatosis. Gonadotropin secretion was studied in seven patients with hemochromatosis and hypogonadism, before and after chronic pulsatile GnRH therapy. Pulsatile LH secretion was studied before (sampling every 10 min for 6 h) and after 15-30 days of chronic pulsatile GnRH therapy (10-12 micrograms per pulse). Prior to GnRH therapy, all the patients had low serum testosterone, FSH and LH levels. LH secretion was non-pulsatile in four patients, while a single pulse was detected in the remaining three. Chronic pulsatile GnRH administration did not increase serum testosterone levels; similarly, serum LH levels remained low: neither pulse frequency nor pulse amplitude was modified. We conclude that hypogonadism in hemochromatosis is due to pituitary lesions.

Lactation, Health, and Reproduction of Dairy Cows Receiving Daily Injectable or Sustained-Release Somatotropin

Seventy-four Holstein cows (26 primiparous) were utilized to compare the efficacy and safety of sustained-release versus daily injectable formulations of recombinant bST. Twenty-four control cows were injected biweekly with oil microsphere; 25 cows were injected biweekly with 350mg of bST microsphere; and 25 cows were injected daily with 10.3mg of bST. Injections were initiated between wk 4 and 5 of lactation and continued for 280 d. Administration of bST caused a moderate increase in milk and FCM production and improved the efficiency of feed and energy conversions. Most health-related and reproduction-related variables did not differ among treatment groups. However, incidence of teat and udder disorders and feet and leg problems tended to be higher during the 40-wk injection period for the bST-treated cows than for the control cows. Incidence of GnRH therapy and number of days to first service were higher for daily bST-treated cows than for controls. No differences existed between sustained-release and daily bST-treated cows for any parameters monitored.

The response of uterine fibroids to GnRH-agonist treatment can be predicted in most cases after one month

Twenty-seven patients with uterine fibroids were treated for 3 months with the GnRH-agonist goserelin prior to surgical myomectomy. Ovarian function was suppressed reliably in all patients. After three applications, 15 fibroids were reduced in volume by more than 50%, and one complete remission was achieved. Seven patients showed a decrease of 10–50% in volume. However, in 5 cases there was no significant reduction. Analysing the time course of the fibroid reduction, the response can be predicted in most cases as early as four weeks after the first injection. Retrospective statistical analysis showed that a 50% reduction in fibroid size due to GnRH treatment is preceded by a 35% reduction after 4 weeks in 81% of cases, and after 8 weeks in all cases. Only 2 of 12 fibroids, which showed a smaller response (< 50%) to GnRH therapy, were reduced by more than 35% after 4 and 8 weeks. In most cases it seems to be possible to estimate the individual response to GnRH-application after the first injection, so that it is possible to stop therapy in non-responding patients.

Endocrine Abnormalities and Hormonal Therapy

Routine measurement of estrogens, testosterone, T4, insulin, FSH, and LH at least four times per year (e.g., during each of the four seasons) may improve the efficiency of stallion management. Benefits may not be realized in the short term but will provide valuable historical data on individual stallions that, when added to other data, will improve ability of management personnel to initiate early treatment and delay or slow declining fertility. This ability will be greatly improved as more data and products become available. There appears to be a relationship between low total estrogen concentration/high FSH concentration and subfertility. This condition is associated with high average breedings per pregnancy. A decrease in concentration of estrogen and an increase in FSH concentration often precede a decline in fertility associated with oligospermia. Hypogonadotropic stallions have not been reported. This condition is not likely to be a cause of declining fertility in stallions and greatly limits the potential efficacy of GnRH therapy in subfertile stallions. Much research must be done to elucidate the etiology of testicular degeneration associated with increased FSH concentrations and decreased estrogen concentrations in stallions. At present, no reliable hormonal therapeutic protocols exist that will improve fertility in subfertile stallions.

Progesterone stimulates luteinizing hormone secretion by acting directly on the pituitary.

To determine if progesterone (P) does affect gonadotropin secretion by acting directly on the pituitary, six women with hypothalamic gonadotropin deficiency were studied. They were treated with 17 beta-estradiol (E2; 2 mg/day, orally) to induce P receptors and maintain constant plasma E2 levels during two 15-day periods separated by 1 month. GnRH was administered iv at a dose of 10 microgram/pulse every 90 min during the last 5 days of E2 treatment. Either P (400 mg/day) or a placebo was administered intravaginally in a cross-over randomized design during the 5 days of pulsatile GnRH therapy. A baseline study of pulsatile LH secretion was performed, with sampling performed every 10 min for 8 h. The sampling was then repeated on day 15 of each study period at the end of pulsatile GnRH administration. Plasma levels of E2 and P were measured every day during the 5 days of either GnRH and P or GnRH and placebo treatment. In the six patients, the observed apulsatile pattern of LH during the baseline study confirmed the diagnosis of complete gonadotropin deficiency. Plasma E2 levels were not significantly different at the time of each pulse analysis (288 +/- 61 vs. 252 +/- 77 pmol/L). The plasma P level achieved with the vaginal pessaries was 22 +/- 5 nmol/L. P treatment resulted in all cases in a significant increase in the mean plasma LH level (5.2 +/- 0.9 vs. 3.6 +/- 0.7 IU/L after GnRH plus placebo; P less than 0.001). Furthermore, LH pulse amplitude was significantly increased by P compared to placebo (3.1 +/- 0.3 vs. 1.4 +/- 0.1 IU/L, respectively; P less than 0.01). Mean plasma FSH levels were significantly increased by GnRH regardless of whether P or placebo was present. In conclusion, these data indicate that a short exposure to physiological levels of P in the range of early luteal phase levels has a stimulatory effect on LH secretion by acting directly at the pituitary level.

Effects of decreasing exogenous GnRH pulse frequency on FSH and inhibin secretion in men with idiopathic hypogonadotropic hypogonadism

The potential importance of GnRH pulse frequency modulation and steroid or inhibin negative feedback in the selective control of pituitary FSH secretion was investigated in 5 adult men with idiopathic hypogonadotropic hypogonadism in whom plasma testosterone has been previously normalized by pulsatile GnRH therapy. The effects of decreasing frequency of pulsatile iv GnRH administration from 2- to 4-hourly for 7 days were examined at constant GnRH bolus dose or constant daily dose and also with interrupted gonadal steroid feedback using a combination of an anti-androgen (flutamide 250 mg t.i.d.) and an aromatase inhibitor (aminogluthetimide 125 mg b.d.) orally for a further 7 days. Slowing GnRH pulse frequency from 2- to 4-hourly did not alter mean plasma FSH at constant bolus dose or constant total daily doses of GnRH. In two subjects with subnormal but not in another two with normal testicular volumes, FSH rise was observed when the 4-hourly GnRH pulse frequency was combined with the interruption of steroid feedback. These results are not compatible with a major role for GnRH pulse frequency modulation in the regulation of pituitary FSH secretion in the presence of normal gonadal steroid feedback. Irrespective of FSH concentrations, plasma inhibin immunoactivity did not change significantly with the alteration in GnRH pulse frequency. The role of inhibin in the control of FSH therefore remains undefined in men.

Ultrasonic and endocrinologic aspects in gonadotropin releasing hormone induction of ovulation

Ovarian growth, follicular size, 17 beta-estradiol (E2), androstenedione (A) and testosterone (T) peripheral levels were evaluated in 12 hypogonadotropic patients during the follicular phase on 12 cycles of pulsatile GnRH iv administration. During GnRH therapy, significant correlations between E2 plasma levels and volume of the dominant follicle (p less than 0.001) as well as total follicular volume (p less than 0.001) and total ovarian volume (p less than 0.01) were found. Plasma A was significantly related to the ultrasonic changes of ovarian stroma and those follicles which usually fail to ovulate. Plasma T showed a significant correlation with ovarian stroma (p less than 0.05). Significant correlations of E2/A and E2/T peripheral ratios with volume of the dominant follicle (p less than 0.01) were also found. In spontaneous ovulatory cycles, similar correlations between endocrine and morphological parameters have been already published. The findings of the present investigation indicate that in spontaneous and GnRH-induced cycles the endocrine events associated to the follicular development are quite similar. In hypogonadotropic patients, a "normal" follicular maturation may be obtained by means of this therapy.

Pregnancy following regression of uterine submucosal leiomyoma with GnRH therapy; a case report

A patient with a history of two spontaneous abortions, at the 16th and 20th week, respectively, and one intra-uterine fetal death at the 26th week of gestation was investigated. The sole abnormal condition that could be evidenced was a submucosal leiomyoma of 56 mm in diameter in the uterine fundus. Administration of gonadotropin/releasing hormone analog (GnRHa) for 10 months resulted in complete disappearance of myoma. Direct intraperitoneal insemination following induction of ovulation resulted in pregnancy. In a patient harboring uterine leiomyomas, adversly affecting conception and pregnancy outcome, GnRHa treatment may be an initial approach allowing to avoid pelvic surgery. As the beneficial effect of GnRHa might be temporary, assisted reproduction procedures might anticipate conception.

Management of Ovulatory Disorders with Pulsatile Gonadotropin-Releasing Hormone*

Pulsatile GnRH therapy has yet to achieve widespread acceptance as an alternative to exogenous gonadotropin therapy in women with hypothalamic amenorrhea and complete GnRH deficiency. However, when a physiologically based replacement regimen of pulsatile GnRH is used, a high rate of ovulation and conception can be anticipated in patients with complete GnRH deficiency and hypothalamic amenorrhea. Women with polycystic ovarian syndrome may also benefit from pulsatile GnRH, although rates of ovulation are lower. Pretreatment with a GnRH agonist may improve these rates considerably, but experience is limited. Whether an iv or sc route of administration is chosen, a simplified clinical monitoring protocol can be created which requires a minimum of patient monitoring while assuring maximum safety. Seventy five nanograms per kg appears to be a reasonable initiating dose, with subsequent increases in those who do not respond. The frequency of GnRH administration is best based on the GnRH pulse frequency in normal women. However, further information is needed to determine whether such a variable frequency is clearly superior to a fixed frequency regimen. When used appropriately, pulsatile GnRH is safe, effective, and offers an excellent alternative to conventional gonadotropin therapy for women with disordered endogenous GnRH secretion. Most importantly, and as opposed to exogenous gonadotropin therapy, pulsatile GnRH can be administered by most physicians in the office setting without the necessity of on-line E2 monitoring. This feature will enable more patients to receive treatment by their local physicians, whereas exogenous gonadotropin therapy should be administered by appropriately equipped referral centers. In the future, further studies will be required to determine which other categories of patients might benefit from pulsatile GnRH.

12 Common problems in induction of ovulation

There are many groups of women with anovulatory infertility who respond abnormally to conventional treatment. It is important to diagnose the underlying disorder correctly before commencing treatment. In this chapter we have discussed the various treatment modalities available and how they may be adapted to fit the particular clinical needs. In women who are profoundly hypo-oestrogenic, the 'priming' of the ovary using prolonged low-dose gonadotrophins offers a possible solution if both subcutaneous and intravenous pulsatile GnRH therapy has failed. It may also reduce the incidence of multiple pregnancies in these women. Growth hormone seems to augment the response to gonadotrophin in these women and may prove a useful adjunct to therapy once further experience of its use has been reported. Women with PCO have been a difficult group to treat because of their tendency to hyperstimulate. The low-dose gonadotrophin regimen outlined in this chapter overcomes the majority of these problems without reducing the rate of conception. This group continue to have an increased incidence of miscarriage. The introduction of combined therapy of hMG with a GnRH analogue may improve this situation, but the data from randomized controlled studies are still awaited. Ovarian failure remains an untreatable cause of infertility. A few women may become pregnant spontaneously, but these are the exception rather than the rule. Hormone replacement therapy should be offered to all these women because of the long-term problems of osteoporosis and cardiovascular disease. Products containing a low dose of oestrogen (e.g. Premarin 0.625 mg) will not interfere with ovulation if there should be a spontaneous resumption of ovarian activity.

GnRH therapy in a stallion of low fertility

An 18-year-old Quarter Horse stallion that was clinically diagnosed as undergoing testicular degeneration was treated with daily injections of 500 gm GnRH (LHRH, Sigma L7134). Prior to treatment, plasma LH, FSH and testosterone concentrations were normal. During therapy, testosterone declined to very low concentrations. The semen parameters stabilized and no further decline was observed. A slight improvement in motility, total number of spermatozoa per collection and thus, total number of motile sperm was observed during treatment when compared with the previous years data.