Long-acting GnRH Agonist Research Articles

Effect of prolonged gonadotropin-releasing hormone agonist therapy on the outcome of rapid ICSI-ZIFT in patients with endometriosis

Objective: We presented 4000 cases of intrafallopian transfer of ova immediately after intracytoplasmic sperm injection (RAPID ICSI-ZIFT) for treatment of severe male factor infertility in 57th annual meeting of ASRM 2001, in the present study we want to evaluate the effect of a 3 month course of GNRH agonist administered immediately before RAPID ICSI-ZIFT in infertile patients with endometriosis. Design: Prospective randomized trial in a private and university ART center. Materials and Methods: 50 patients received three courses of a long-acting GNRH agonist. Triptorelin lactide (Decapeptyl Pharma Biotech-sines France) 3.75 mg IM every 28 days followed by standard controlled ovarian hyperstimulation. Fifty two patients received standard controlled ovarian hyperstimulation with midluteal phase GNRH agonist down regulation. Candidates were infertile patients with endometriosis and at least one patent fallopian tube documented at laparoscopy within 60 months of cycle initiation (Range 2–55 months). All patients had regular menses (every 26–33 days). Patients with early follicular phase greater than 12 mIU/ml and evidence of ovarian endometrioma were excluded. Patients were randomized into two groups by using a computer generated random number (IRB approved). Group 1 consisted of 50 patients who received a depot preperation of the GNRH agonist Decapeptyl 3.75 mg IM. every 28 days for three injections. The first injection was administered during the early follicular phase. Controlled ovarian hyperstimulation consisted of standard GNRH agonist down-regulation using LH/RH agonist buserlin (suprefact) HMG combinations in the form of a long protocol and transvaginal ultrasound guided oocyte retrieval, ICSI and laparoscopic tubal transfer within 45 days of the last decapeptyl injection. Group 2 consisted of 52 controls with endometriosis who did not receive the long-acting GNRH agonist but instead underwent standard controlled ovarian hyperstimulation regimens. Results: Baseline clinical data did not differ significantly in terms of age (Y), group I, 33.12 ± 0.67 (Range 28–39) group II, 32 ± 0.56 (Range 27–39) early follicular phase serum FSH group I, 6.17 ± 0.54 mIU/ml group II, 7.32 ± 0.32. Estradiol group I, 36.26 ± 5.37 (pg/ml) group II, 30.33± 4.84. Interval between the most recent surgical intervention and cycle onset group I, 14.52 ± 2.45 (MO) group II, 17.58 ± 2.4 (MO) surgical technique used, however significantly greater proportion of group I patients than group II patients had stages III or IV endometriosis. Group I, 21 and group II, 15 (p<0.05). The groups did not differ with regard to total Gonadotropin dose. Group I, 42 ± 3.21 (75 IU Ampules) or days of administration. Group I, 10.12 ± 0.43 and group II, 10.08 ± 0.21, number of oocytes obtained, group I, 14.84 ± 1.5, group II, 15.23 ± 1.56 number of embryo transferred. Group I, 3.28 ± 0.19 and group II, 3.04 ± 0.2. The implatation rate in group I, was 38.7% and only 20.2% in group II (p-value = 0.002). The clinical pregnancy rates were 45.5% and 18.6%, respectively (p-value = 0.007). Conclusion: The pregnancy and implantation rates were significantly higher in prolonged gonadotropin-releasing hormon agonist therapy on the outcome of Rapid ICSI-ZIFT in patients with endometriosis.

A pilot study of the use of low dose human menopausal gonadotropin in ovulation induction

Objective: To evaluate the clinical efficacy of a combined regimen of follicle stimulating hormone (FSH) and low dose human menopausal gonadotropin (hMG) following GnRH agonist ultralong protocol in controlled ovarian hyperstimulation (COH) for in vitro fertilization and embryo transfer (IVF-ET). Study design: IVF-ET was performed on 45 patients who had uterine or peritoneal factors, such as moderate to severe endometriosis, adenomyosis, or uterine myoma. The patients were randomized into two groups after the administration of long-acting GnRH agonist 2–4 times within a 4-week interval; highly purified FSH (FSH-HP) and hMG (Group A, n=26), FSH-HP only (Group B, n=19). hMG was administered at a fixed-dose of 75 IU per day and the dose of FSH-HP was adjusted according to the patient’s individual response. The results of COH and IVF-ET were assessed and compared between the two groups. Results: Serum estradiol (E 2) level on hCG day was significantly higher in Group A (1418.2±920.2 pg/ml, mean±S.D.) than in Group B (678.4±457.8 pg/ml) ( P<0.05). The clinical pregnancy rate and implantation rate tended to be higher in Group A than in Group B; 23.1% (6/26) versus 10.5% (2/19), 11.0% (9/82) versus 4.6% (3/65). Conclusion: In COH for IVF-ET using GnRH agonist ultralong protocol, the combined treatment of FSH-HP and low dose hMG showed a higher serum E 2 level when compared with treatment with FSH-HP alone.

Effects of prenatal treatment with antiandrogens on luteinizing hormone secretion and sex steroid concentrations in adult spotted hyenas, Crocuta crocuta.

Prenatal androgen treatment can alter LH secretion in female offspring, often with adverse effects on ovulatory function. However, female spotted hyenas (Crocuta crocuta), renowned for their highly masculinized genitalia, are naturally exposed to high androgen levels in utero. To determine whether LH secretion in spotted hyenas is affected by prenatal androgens, we treated pregnant hyenas with antiandrogens (flutamide and finasteride). Later, adult offspring of the antiandrogen-treated (AA) mothers underwent a GnRH challenge to identify sex differences in the LH response and to assess the effects of prenatal antiandrogen treatment. We further considered the effects of blocking prenatal androgens on plasma sex steroid concentrations. To account for potential differences in the reproductive state of females, we suppressed endogenous hormone levels with a long-acting GnRH agonist (GnRHa) and then measured plasma androgens after an hCG challenge. Plasma concentrations of LH were sexually dimorphic in spotted hyenas, with females displaying higher levels than males. Prenatal antiandrogen treatment also significantly altered the LH response to GnRH. Plasma estradiol concentration was higher in AA-females, whereas testosterone and androstenedione levels tended to be lower. This trend toward lower androgen levels disappeared after GnRHa suppression and hCG challenge. In males, prenatal antiandrogen treatment had long-lasting effects on circulating androgens: AA-males had lower T levels than control males. The sex differences and effects of prenatal antiandrogens on LH secretion suggest that the anterior pituitary gland of the female spotted hyena is partially masculinized by the high androgen levels that normally occur during development, without adverse effects on ovulatory function.

Fas and its ligand, caspases, and bcl-2 expression in gonadotropin-releasing hormone agonist-treated uterine leiomyoma.

GnRH agonist (GnRH-a) therapy is known to shrink uterine leiomyoma, although the molecular mechanisms responsible for this effect remain poorly understood. Conflicting results exist as to whether GnRH-a treatment increases apoptosis in leiomyoma cells. The aim of this study is to investigate the effects of GnRH-a on uterine leiomyomas by profiling the expression levels of apoptosis-related molecules such as Fas/Fas ligand (FasL), caspases 3, 6, 7, 8, 9, and 10, and Bcl-2 from specimens of 20 patients receiving Leuplin Depot (LA), a long-acting GnRH-a, of 3 doses before myomectomy, as well as 24 controls. We found that uterine leiomyomas had up-regulated expressions of FasL and caspase 3 as compared with their homologous normal myometrium control. Both leiomyomas and myometria from LA-treated patients, however, presented a significant decrease in the expressions of FasL and caspase 3 as compared with those from LA-naive control patients. In addition, it was at the posttranscription level that the tumorigenesis of leiomyoma modulated the expressions of FasL and caspase 3 higher, whereas LA suppressed them at gene transcription. Unlike the case of FasL and caspase 3 mentioned above, no significant difference was found between leiomyomas and homologous myometria in the expressions of Fas and caspases 6, 7, 8, 9, and 10. The LA effect made drug-treated leiomyomas produce less Fas and caspases 7, 9, and 10 as compared with nontreated leiomyomas. Immunohistochemical analysis showed that both Fas and FasL were localized predominantly in cytosol. Moreover, leiomyomas had an up-regulated Bcl-2 level, which remained high even in the LA-treated cells. Our findings provide molecular evidence to support our previous observations that GnRH-a therapy fails to increase apoptosis in uterine leiomyomas.

Effect of prolonged gonadotropin-releasing hormone agonist therapy on the outcome of in vitro fertilization-embryo transfer in patients with endometriosis

Objective: To evaluate the effect of a 3-month course of GnRH agonist administered immediately before IVF-ET in infertile patients with endometriosis. Design: Prospective, randomized trial. Setting: Three tertiary care assisted reproductive technology programs. Patient(s): IVF-ET candidates with surgically confirmed endometriosis. Intervention(s): Twenty-five patients received three courses of a long-acting GnRH agonist, 3.75 mg i.m. every 28 days, followed by standard controlled ovarian hyperstimulation. Twenty-six patients received standard controlled ovarian hyperstimulation with mid-luteal phase GnRH agonist down-regulation or microdose flare regimens. Main Outcome Measure(s): Response to controlled ovarian hyperstimulation, ongoing pregnancy rates per cycle, group implantation rates, and implantation rate per embryo transfer procedure. Result(s): The extent of surgically confirmed endometriosis was greater in patients who received the long-acting GnRH regimen for 3 months before IVF-ET. The groups did not differ significantly in terms of dose or duration of gonadotropin stimulation, number of oocytes retrieved, fertilization rate, or number of embryos transferred. Patients who received the long-acting GnRH regimen had significantly higher ongoing pregnancy rates (80% vs. 53.85%) and a trend toward higher implantation rates (42.68% vs. 30.38%). Conclusion(s): Prolonged use of GnRH agonist before IVF-ET in patients with endometriosis resulted in significantly higher ongoing pregnancy rates than did standard controlled ovarian hyperstimulation regimens. No deleterious effect on ovarian response was observed.

More effective induction of spawning with long-acting GnRH agonist in the shi drum, Umbrina cirrosa L. (Sciaenidae, Teleostei), a valuable candidate for Mediterranean mariculture

Three experiments of spawning induction in shi drum, Umbrina cirrosa L., were performed in six different commercial Italian hatcheries from May to August (water temperatures: 19–29 °C; salinity: 21–37 p.p.t.). In the first experiment, 119 females (1–4.7 kg), subdivided into 29 lots, were injected with a single dose (2, 5, 8, 10, 15 and 20 μg kg−1 body weight) of short-acting gonadotropin- releasing hormone agonist (GnRHa-S), des-Gly10,[D-Ala6]-LH-RH ethylamide. In the other two experiments, 85 females (0.7–5.8 kg), subdivided into 22 and four lots, were treated with one (40 or 80 μg kg−1) or three doses (40 μg kg−1) of long-acting GnRHa (GnRHa-L), respectively. GnRHa-S stimulated spawning in 69% of the 29 treated lots; the number of eggs laid reached a maximum of 130 000 and a weighted mean of 29 200 total eggs kg−1. GnRHa-L elicited a spawning response in 95% of the 22 one-dose treated lots; the number of laid eggs was higher than with GnRHa-S, reaching a maximum of 213 100 and a weighted mean of 59 400 total eggs kg−1. The yield of developing embryos in 67% of the single GnRHa-L treatments was higher (sometimes up to three times) than with GnRHa-S. Triple treatments of the four lots of females with GnRHa-L always resulted in spawning responses; the best result corresponded to a number of total laid eggs of 358 900 eggs kg−1 with a yield of 177 300 developing embryos.

Progesterone serum levels during the follicular phase of the menstrual cycle originate from the crosstalk between the ovaries and the adrenal cortex

The preovulatory rise of progesterone is important for ovulation, but both its regulation and its origin are controversial. Three experiments were performed to determine whether follicular phase progesterone arises from the ovary, the adrenal cortex or both. The first study was performed in patients scheduled for assisted reproduction, who received a long-acting GnRH agonist either during intake of an oral contraceptive or during the luteal phase of an otherwise untreated menstrual cycle. The second study was also performed during down-regulation with a GnRH agonist: some patients with elevated progesterone levels received dexamethasone (DXM). Others with similarly elevated basal progesterone levels and those with low progesterone levels were not treated with DXM and served as controls. Finally, adrenocorticotrophic hormone (ACTH) tests were performed in normocyclic volunteers both during early and late follicular phase and during intake of a contraceptive pill. During the suppression of endogenous gonadotrophin secretion progesterone levels rose after the administration of ACTH, but not of GnRH. DXM did not prevent the preovulatory rise of the serum progesterone concentration. The ACTH-stimulated concentration of progesterone and of 17alpha-hydroxyprogesterone were significantly reduced during intake of ethinyl estradiol. Progesterone arises in the adrenal cortex during most of the follicular phase, whereby its function is modulated by an unknown ovarian factor, which is suppressed by ethinyl estradiol. The source of progesterone shifts towards the ovaries prior to ovulation.

Superovulation using recombinant human FSH and ultrasound-guided transabdominal follicular aspiration in baboon ( Papio anubis)

The response of baboon females to a modified human ovarian stimulation protocol incorporating start of pituitary suppression in the luteal phase of the cycle with a GnRH agonist (GnRHa) and recombinant human FSH (rhFSH) was studied. A long-acting GnRHa implant supplying goserelin acetate was administered s.c. to six adult female baboons experiencing regular menstrual cycles (33–34 days) on days 22–24 of the cycle. Follicular development was monitored by transabdominal ultrasonography and serum levels of E2 and progesterone (P4) and rhFSH were determined by ELISA. Menses occurred 9–10 days after GnRHa administration. Daily i.m. administration of 75 IU rhFSH commenced 9–10 days after menses and continued for 9–10 days. When most follicles were ≥5 mm diameter and serum E2 had reached its maximum level, 2000 IU hCG was administered i.m. to induce follicle maturation. Transabdominal ultrasound-guided follicular aspiration of follicles ≥2 mm diameter was performed 30–34 h after hCG administration. One baboon did not show an adequate response to rhFSH stimulation. This animal did not receive further treatment and no data for it are presented. The number of follicles aspirated was 21±4 and 17.2±3.8 oocytes were recovered per animal with an average recovery rate of 82% (86/105). The number of oocytes collected from five animals were 14, 21, 16, 15, and 20 ( n=86). Most of the oocytes recovered were in metaphase II and 3 h after recovery 91% (78/86) were considered suitable for in vitro fertilization. It was concluded that recombinant human FSH can successfully induce follicular recruitment and oocyte maturation in baboon females during pituitary suppression with a GnRHa

Management and outcome of central precocious puberty

Management and outcome of central precocious puberty

Controlled ovarian stimulation and ultrasound guided follicular aspiration in the baboon (Papio cynocephalus anubis).

The objective of this study was to investigate whether baboon females respond to an ovarian stimulation protocol incorporating pituitary suppression with a GnRH agonist (GnRHa) and highly purified human FSH (hphFSH) with follicular development and oocyte maturation. An ovulation induction protocol was applied to 5 adult female baboons with a history of regular menstrual cycles (33-34 days). A long-acting GnRHa implant containing goserelin acetate was placed s.c. on days 22-24 of their menstrual cycle. Daily hphFSH (75 IU im) treatments were started approximately 10 days following menses. When the majority of the follicles were > or = 5 mm in diameter and the E2 levels had reached a maximum, hCG (2000 IU i.m.) was administered to induce final maturation of the oocytes and ovulation. 30 to 34 h after hCG administration, transabdominal follicular aspiration was performed using a variable frequency transvaginal transducer with ultrasound. A total of 71 oocytes were collected (average: 17). 91% of the oocytes were morphologically normal indicating that they were appropriate for in vitro insemination.

Ovarian stimulation and ultrasound-guided oocyte retrieval in baboon (Papio Cynocephalus Anubis) during pituitary suppression with a GnRH agonist.

The objective of this study was to investigate whether baboon females respond to an ovarian stimulation protocol incorporating pituitary suppression with a GnRH agonist (GnRHa) and either highly purified human FSH (hphFSH) or recombinant human FSH (rhFSH) with follicular development and oocyte maturation. A modified human ovulation induction protocol was applied to 5 adult female baboons with a history of regular menstrual cycles (33-34 days). A long-acting GnRHa implant containing goserelin acetate was placed subcutaneously (s.c.) on Days 22-24 of their menstrual cycle. Concentrations of serum oestradiol (E2), progesterone (P4) and human FSH were obtained by ELISA. Menses occurred approximately 10 days after GnRHa implantation. Daily hphFSH or rhFSH (75 IU i.m.) treatments were started approximately 10 days following menses. When the majority of follicles were > or = 5 mm in diameter and the E2 levels had reached a maximum, hCG (2000 IU i.m.) was administered to induce final maturation of oocytes and ovulation. Thirty to 34 h after hCG administration, transabdominal follicular aspiration was performed using a variable frequency transvaginal transducer with ultrasound. A total of 71 oocytes were collected from 4 animals (average: 17). The meiotic maturity of oocytes was evaluated 3 h after retrieval. Ninety-one percent of oocytes were in metaphase 2 and of grades I and II which are appropriate for in vitro insemination.

Long-term use of gonadotropin-releasing hormone analogs and hormone replacement therapy in the management of endometriosis: a randomized trial with a 6-year follow-up

Objective: To identify the effects of long-term GnRH agonist use (6–24 months), with and without add-back therapy, and spontaneous reversibility of bone mass density (BMD) up to 6 years after treatment. Design: A prospective, randomized, long-term follow-up study. Setting: Obstetrics and gynecology department in a university hospital in the United Kingdom. Patient(s): Forty-nine symptomatic women with a laparoscopic diagnosis of endometriosis who had been identified for treatment with long-acting GnRH agonist and volunteered to participate in the study. Intervention(s): Women were randomly allocated to receive hormone replacement therapy (HRT) as a daily oral dose of estradiol, 2 mg, and norethisterone acetate, 1 mg, or no treatment in addition to monthly subcutaneous implants of goserelin acetate for up to 2 years, until cessation of symptoms. Bone mineral density (BMD) at the lumbar spine (C2–C4) and hip (Ward triangle) was measured every 6 months. Main Outcome Measure(s): BMD changes in both groups. Result(s): 45 women were followed up for 6 years, at the end of which the groups did not differ significantly in the reduction in mean BMD at the lumbar spine or hip. Conclusion(s): BMD reduction occurs during long-term GnRH agonist use and is not fully recovered by up to 6 years after treatment. Use of HRT does not affect this process.

Preventive effects of a herbal medicine on bone loss in rats treated with a GnRH agonist

The study was designed to evaluate the effects of a traditional Chinese herbal medicine Hochu-ekki-to (Bu-zong-yi-qi-tang), which was composed of 10 herbal medicines and had been used for the treatment of oligospermia and as a postoperative medication in Japan, on bone loss in rats treated with a gonadotropin-releasing hormone (GnRH) agonist. Female rats at 40 weeks of age were divided into 4 groups of 8 rats each. In the three experimental groups, each animal received subcutaneous injections of the long-acting GnRH agonist, buserelin acetate, once every four weeks throughout the experiment. Beginning at 48 weeks of age, the experimental groups were given diets containing conjugated estrogens or Hochu-ekki-to for 8 weeks. The administration of the GnRH agonist reduced the bone mineral density in the whole femur to 91.0% of that in the control group. However, administration of conjugated estrogens and Hochu-ekki-to increased the serum concentrations of estradiol 16.8- and 5.3-fold respectively compared with concentrations in the GnRH agonist-treated group, resulting in the augmentation of the bone mineral density to 110.3% and 106.2% respectively. These findings indicate that Hochu-ekki-to enhances the reduced bone mineral density and causes a slight elevation of the serum estradiol levels in the chemically castrated rats.

Hormonal and clinical effects of chronic gonadotropin-releasing hormone agonist treatment in polycystic ovary syndrome

The aim of the study was to evaluate the hormonal (focusing on the urinary steroid profile) and clinical effects of chronic gonadotropin-releasing hormone (GnRH) agonist treatment in patients with polycystic ovary syndrome (PCOS) suffering from hirsutism. A long-acting GnRH agonist was administered for 6 months in eight PCOS patients. Hormonal effects were measured by determining serum luteinizing hormone (LH), follicle stimulating hormone (FSH), prolactin, testosterone and estradiol concentrations, and by profiling urinary steroids using capillary gas chromatography of 24-hour urine samples. To evaluate 5α-reductase enzyme activity, the ratios of androsterone to etiocholanolone and 5α-tetrahydrocortisol to tetrahydrocortisol were calculated in urine samples. The ratio of androgen to Cortisol metabolites was also determined before, and 3 and 6 months after therapy.LH and estradiol levels were suppressed significantly after the first injection and testosterone after the second injection of the GnRH agonist. Thus, serum testosterone was normalized. Ratios of urinary steroids reflecting 5α-reductase enzyme activity (androsterone to etiocholanolone and 5α-tetrahydrocortisol to tetrahydrocortisol) and the ratio of androgen to Cortisol metabolites decreased significantly after 3 months of treatment. Degree of hirsutism, assessed by Ferriman-Gallwey score, diminished after 6 months, but not significantly.In conclusion, our data show that long-acting GnRH agonist treatment of PCOS patients is effective in reducing serum and urinary androgen levels, but it is not accompanied by an effective reduction in hirsutism during a 6-month treatment period. A longer or a combined treatment would be needed to achieve significant improvement in hirsutism. Gas chromatographic profiling of urinary steroids and the use of specific ratios of the excreted metabolites seems to be a sensitive tool both in the diagnosis of PCOS and in monitoring ovarian suppression.

Hormonal and clinical effects of GnRH agonist alone, or in combination with a combined oral contraceptive or flutamide in women with severe hirsutism

The objective of this prospective randomized study was to evaluate and compare the hormonal and clinical effects of long-acting gonadotropin-releasing hormone (GnRH) agonist and a combination of GnRH agonist with combined oral contraceptive (COC) or flutamide in women with polycystic ovary syndrome (PCOS).Thirty-five hirsute women with PCOS, ranging in age from 19–27 years, were randomly divided into three groups: group A treated with GnRH agonist (n = 12), group B (n = 12) treated with GnRH agonist plus COC and group C (n = 11) treated with GnRH agonist plus flutamide for 6 months. Before, at the end and 6 months after the end of treatment, blood samples were drawn from all women (in early follicular phase in those with menstrual cycles) to measure ovarian and adrenal androgens, gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH), estradiol and estrone plasma levels.The results showed that all three protocols had good therapeutic efficacy. A significant reduction in hirsutism was observed in all patients after 6 months of therapy, the Ferriman–Gallwey scores dropping to 9 ± 3 in group A, 10 ± 4 in group B and 11 ± 5 in group C. Six months after the end of therapy, the hirsutism score continued to be significantly reduced in all groups. After 6 months of therapy, a reduction in plasma levels of LH, FSH, estrone, estradiol, testosterone, free testosterone, androstenedione and dehydroepiandrosterone sulfate (DHEAS) was observed in all groups although this was more pronounced in group B and group C.These therapies may be the basis of future treatments that quickly reduce hirsutism and remove its causes by reducing the secretion of ovarian and adrenal androgens and by blocking androgen receptors.

Pharmacotherapy of paraphilias in the next millennium.

Paraphilias are psychiatric disorders of abnormal sexual behavior whose prevalence has markedly increased during the last decade. Treatment modalities currently used fall into three categories: surgical castration, psychotherapy, and pharmacotherapy. The pharmacological interventions consist of antiandrogens that either completely reduce testosterone secretion and/or antagonize the action of testosterone at the level of the receptor, and psychotropic drugs, namely antidepressants. Cyproterone and medroxyprogesterone acetates are the two antiandrogens more commonly used. They are only effective in relatively high doses, but have a substantial number of severe side effects which has considerably limited their use. Psychotropic drugs may be effective solely in men with a definite obsessive-compulsive disorder component. Because of the erratic results and lack of permanent eradication of the paraphilic manifestations their use in paraphilias is highly controversial. Long-acting gonadotropin-releasing hormone (GnRH) agonist analogues are the most potent antiandrogens, and selectively abolish testosterone secretion in a totally reversible fashion. They are administered parenterally once every 1 to 3 months, and have the fewest side effects. Long-acting GnRH analogues, together with psychotherapy, are highly effective in controlling selected paraphilias (pedophilia, exhibitionism, and voyeurism), and are the most promising mode of therapy in the next millennium. There is an urgent need for good methodological research; carefully designed double-blind controlled studies with a large number of subjects in order to validate or not the use of the various pharmacotherapies.

The antigonadotropic activity of a 19-nor-progesterone derivative is exerted both at the hypothalamic and pituitary levels in women.

We have previously shown in postmenopausal women that a 19-nor-progesterone derivative, nomegestrol acetate (NOMA) had a strong antigonadotropic activity and that this effect was not mediated via the androgen receptor. The aim of the present study was to further assess the action of this progestin on gonadotropin secretion in women. To demonstrate at which level of the hypothalamo-pituitary-ovarian axis the gonadotropin inhibition was exerted, 10 normally cycling (NC) women, 3 women with a gonadotropin-independent ovarian function [McCune-Albright (MCA) syndrome], and 5 women with functional hypothalamic amenorrhea (FHA) participated in the study. NC women were treated orally with 5 mg NOMA for 21 days, after one control cycle. Plasma estradiol (E2) and progesterone, LH, and FSH levels were measured during each cycle. A frequent sampling study (every 10 min for 4 h), followed by a classic GnRH test (100 microg, i.v.), was performed on day 11. Women with MCA were studied before, during NOMA, and after long-acting GnRH agonist administration. In women with FHA, pulsatile GnRH (20 microg s.c., every 90 min) was given for two cycles with or without NOMA (5 mg for 21 days). In all NC women, ovulation was suppressed by NOMA. Mean plasma LH levels, LH pulse frequency, and the LH response to exogenous GnRH were significantly decreased. In MCA, neither NOMA nor GnRH agonist modified multiple ovarian cysts on ultrasound or plasma E2, levels which remained elevated, ruling out a direct ovarian effect. In FHA, pulsatile GnRH administration recreated a normal ovulatory menstrual cycle. Addition of NOMA prevented the increase of plasma E2, decreased the amplitude of LH pulses, and prevented ovulation. In view of this unexpected action of NOMA at the pituitary level, seven samples of normal human female pituitaries were tested for the presence of progesterone receptor (PR) using a double labeling immunocytochemical technique. The presence of PR was detected in the seven human pituitary tissues. In addition, PR was found to be expressed only in gonadotroph cells. In conclusion, NOMA, a 19-nor-P derivative, has a potent antigonadotropic activity exerted at the hypothalamic level, inhibiting ovulation in NC women. In women with FHA, NOMA decreased the gonadotropin stimulation induced by pulsatile GnRH administration. According to the presence of PR in gonadotroph cells of normal human pituitaries, 19-nor-progesterone derivatives may also act on the gonadotropin secretion at the pituitary level.

Managing a Patient with Presumed Testosterone-Secreting Ovarian Tumor

We report the case of a 70-year-old woman who was presumed to have right ovarian testosterone-secreting tumor and was treated with long-acting gonadotropin-releasing hormone agonist therapy plus add-back hormone replacement therapy. The patient presented with various medical problems including hypertension, intracranial hemorrhage, myocardial infarction, unstable angina pectoris, and poor control of diabetic mellitus and had exhibited rapid symptoms of androgen excess such as progressive hirsutism and bilateral temporal balding for half a year. Tumor survey was negative except for an elevated testosterone level. Renal vein catheterization successfully detected a right ovarian androgen-secreting tumor. Because the patient was deemed medically unable to tolerate surgery, she received an alternative treatment consisting of 6 months of gonadotropin-releasing hormone-agonist (GnRH-a) and add-back hormone replacement therapy (HRT). Serum testosterone levels returned to normal limits after administration of the first dose of GnRH-a. A follow-up tumor survey was negative. The patient has been alive and free of disease for 8 months after six doses of GnRH-a. We conclude that this strategy might be used as urgent therapy in a medically compromised patient with presumed ovarian androgen-secreting tumor.

Endometriosis and infertility: an integrated approach

Objective: To define an integrated approach to endometriosis-associated infertility. Methods: Review of published literature with grading of evidence by quality. Results: Laparoscopy remains the investigation of choice in cases of endometriosis-associated infertility and allows the possibility of surgical ablation at diagnosis. This improves fertility in minimal/mild disease, whereas danazol therapy has no benefit. Both in vitro fertilization (IVF) and superovulation with intrauterine insemination improve fertility in mild/minimal disease. Neither surgery nor medical treatment have been shown to improve fertility in moderate/severe disease. IVF with prolonged pituitary down-regulation produced by long-acting gonadotropin-releasing hormone agonists after surgical debulking offers the best hope in such cases. Conclusions: Endometriosis-related infertility should be treated as rapidly as possible with thorough investigation and the minimum delay between diagnosis and therapy.

Growth hormone advances spermatogenesis in premature rats treated with gonadotropin-releasing hormone agonist.

To clarify the effect of GH on the development of seminiferous tubules in premature male rats, we investigated whether GH accelerates spermatogenesis under the condition of gonadotropin deprivation. Male Wistar rats aged three weeks were divided into three groups and subjected to administration of either long-acting GnRH agonist (GnRHa) or a combination of GnRHa and rat GH, with normal saline solution as control. After the 4-week treatment, sperm density and motility in the right epididymis were measured and seminiferous tubules of right testes were histologically examined. Sperm density and motility were significantly higher in GnRHa+GH-treated rats than in GnRHa-treated rats. In histological examination, the numbers of germ cells in various stages were increased in GnRHa+GH-treated rats compared with GnRHa-treated rats, with the number of mature spermatid being noticeably higher in GnRHa+GH-treated rats. These results suggest that administration of GH decreases loss of germ cells at various stages of spermatogenesis under the condition of gonadotropin withdrawal.