GnRH Agonist Analog Research Articles

GnRH analogs for the treatment of heavy menstrual bleeding associated with uterine fibroids

Treatment of heavy menstrual bleeding associated with uterine fibroids (UF) is evolving. Historically, treatment options were limited to predominantly invasive surgery; today, conservative and novel oral medical treatments are widely available for use with significant efficacy. This evolution was directly driven by our improved understanding of UF pathophysiology. Specifically, our recognition of the hormone-mediated pathway in UF development and growth laid the framework for using GnRH agonist analogs in treating UF. In this report, we explore the use of GnRH analogs in the treatment of heavy menstrual bleeding associated with UF in phases. We review historical perspectives, discuss the development and use of aternatives to GnRH analogs, a period we refer to as the "Dark Ages" of GnRH analogs, we then provide an overview of the later years and present-day use of GnRH analogs and discuss opportunities for future directions.

Fertility concerns of the transgender patient.

Transgender individuals who undergo gender-affirming medical or surgical therapies are at risk for infertility. Suppression of puberty with gonadotropin-releasing hormone agonist analogs (GnRHa) in the pediatric transgender patient can pause the maturation of germ cells, and thus, affect fertility potential. Testosterone therapy in transgender men can suppress ovulation and alter ovarian histology, while estrogen therapy in transgender women can lead to impaired spermatogenesis and testicular atrophy. The effect of hormone therapy on fertility is potentially reversible, but the extent is unclear. Gender-affirming surgery (GAS) that includes hysterectomy and oophorectomy in transmen or orchiectomy in transwomen results in permanent sterility. It is recommended that clinicians counsel transgender patients on fertility preservation (FP) options prior to initiation of gender-affirming therapy. Transmen can choose to undergo cryopreservation of oocytes or embryos, which requires hormonal stimulation for egg retrieval. Uterus preservation allows transmen to gestate if desired. For transwomen, the option for FP is cryopreservation of sperm either through masturbation or testicular sperm extraction. Experimental and future options may include cryopreservation and in vitro maturation of ovarian or testicular tissue, which could provide prepubertal transgender youth an option for FP since they lack mature gametes. Successful uterus transplantation with subsequent live birth is a new medical breakthrough for cisgender women with uterus factor infertility. Although it has not yet been performed in transgender women, uterus transplantation is a potential solution for those who wish to get pregnant. The transgender population faces many barriers to care, such as provider discrimination, lack of information, legal barriers, scarcity of fertility centers, financial burden, and emotional cost. Further research is necessary to investigate the feasibility of experimental FP options, provide better evidence-based information to clinicians and transgender patients alike, and to improve access to and quality of reproductive services for the transgender population.

Gonadotropin Releasing Hormone Agonists or Antagonists for Preimplantation Genetic Diagnosis (PGD)? A Prospective Randomised Trial.

The use of GnRH analogue medication is essential in reproductive medicine to avoid premature ovulation by pituitary suppression for the duration of ovarian stimulation by gonadotrophins. The type of pituitary suppression by either GnRH agonist analogues versus GnRH antagonist analogues may result in different embryological hence clinical results. Preimplantation genetic diagnosis is a subtype of IVF in which embryos are created for genetic diagnosis of hereditary disorders in order to avoid genetically affected children. Embryological quality hence ovarian stimulation in preimplantation genetic diagnosis is crucial as genetic selection will reduce the number of available embryos to a fraction of the total. The aim of this study was to assess the efficiency of GnRH antagonist versus GnRH agonist treatment for pituitary suppression in ovarian stimulation for PGD, by proxy of number and quality of embryos at cleavage stage available for biopsy. We conducted a prospective randomised controlled trial comparing pituitary suppression by GnRH antagonist versus GnRH agonist in ovarian stimulation for PGD. The primary outcome measure was the number of embryos of sufficient quality for biopsy at cleavage stage. Secondary outcome parameters were the number of blastocysts available of top quality, and clinical pregnancy rate. There was no difference in number of oocytes retrieved, embryos at cleavage stage available for biopsy or embryo quality. The clinical pregnancy rate was higher in the GnRH agonist group; however the sample size was insufficient to allow conclusions. The use of GnRH agonist versus antagonist treatment does not result in differences in a number of oocytes, embryos or embryo quality in ovarian stimulation for preimplantation genetic diagnosis.

Protective effect of GnRH analogues on the reproductive capacity of women with neoplasia or autoimmune disease who require chemotherapy. Final results of a phase ii clinical trial

Background and objectiveIn order to avoid the toxic effect of chemotherapy, it has been proposed to use GnRH agonist analogues (GnRHa) to inhibit the depletion of ovarian follicles. Nevertheless, there is controversy about its effectiveness. This clinical trial has been conducted with the aim to assess the protective effect of GnRH analogues on the reproductive capacity of women with malignancies or autoimmune diseases, which require chemotherapy. Patients and methodsOpen phase ii single-center clinical trial. During chemotherapy, a total of 5 doses of GnRH antagonist analogue at a dose interval of 3 days and/or a monthly dose of GnRHa were administered. Hormonal determinations prior to the start of the CT treatment were conducted during treatment and at the end of it. ResultsThe inclusion of patients was prematurely concluded when incorporating the determination of anti-Müllerian hormone (AMH) as a parameter for assessing the ovarian reserve. Out of 38 patients, 23 (60.5%, 95%CI 43.4–76.0) had AMH values below normal following completion of treatment. An intermediate analysis was carried out observing that while most patients were recovering the menstrual cycle (86.6% 95%CI 71.9–95.6), they had reduced levels of AMH. ConclusionAlthough most patients recovered their menstrual cycles, the ovarian reserve, assessed by the concentration of AMH, decreased in many patients. Therefore, we can conclude that the concomitant treatment of chemotherapy and GnRH analogues does not preserve the loss of follicular ovarian reserve.

Efecto protector de los análogos de la GnRH sobre la capacidad reproductiva de las mujeres en edad fértil con neoplasia o enfermedad autoinmunitaria tratadas con fármacos citotóxicos. Resultado final de un ensayo clínico fase II

Background and objectiveIn order to avoid the toxic effect of chemotherapy, it has been proposed to use GnRH agonist analogues (GnRHa) to inhibit the depletion of ovarian follicles. Nevertheless, there is controversy about its effectiveness. This clinical trial has been conducted with the aim to assess the protective effect of GnRH analogues on the reproductive capacity of women with malignancies or autoimmune diseases, which require chemotherapy. Patients and methodsOpen phase ii single-center clinical trial. During chemotherapy, a total of 5 doses of GnRH antagonist analogue at a dose interval of 3 days and/or a monthly dose of GnRHa were administered. Hormonal determinations prior to the start of the CT treatment were conducted during treatment and at the end of it. ResultsThe inclusion of patients was prematurely concluded when incorporating the determination of anti-Müllerian hormone (AMH) as a parameter for assessing the ovarian reserve. Out of 38 patients, 23 (60.5%, 95%CI 43.4-76.0) had AMH values below normal following completion of treatment. An intermediate analysis was carried out observing that while most patients were recovering the menstrual cycle (86.6% 95%CI 71.9-95.6), they had reduced levels of AMH. ConclusionAlthough most patients recovered their menstrual cycles, the ovarian reserve, assessed by the concentration of AMH, decreased in many patients. Therefore, we can conclude that the concomitant treatment of chemotherapy and GnRH analogues does not preserve the loss of follicular ovarian reserve.

Pharmacologic profiles of investigational kisspeptin/metastin analogues, TAK-448 and TAK-683, in adult male rats in comparison to the GnRH analogue leuprolide

Kisspeptin/metastin, a hypothalamic peptide, plays a pivotal role in controlling gonadotropin-releasing hormone (GnRH) neurons, and we have shown that continuous subcutaneous administration of kisspeptin analogues suppresses plasma testosterone in male rats. This study examined pharmacologic profiles of investigational kisspeptin analogues, TAK-448 and TAK-683, in male rats. Both analogues showed high receptor-binding affinity and potent and full agonistic activity for rat KISS1R, which were comparable to natural peptide Kp-10. A daily subcutaneous injection of TAK-448 and TAK-683 (0.008–8μmol/kg) for consecutive 7 days initially induced an increase in plasma luteinizing hormone and testosterone levels; however, after day 7, plasma hormone levels and genital organ weights were reduced. Continuous subcutaneous administrations of TAK-448 (≥10pmol/h, ca. 0.7nmol/kg/day) and TAK-683 (≥30pmol/h, ca. 2.1nmol/kg/day) induced a transient increase in plasma testosterone, followed by abrupt reduction of plasma testosterone to castrate levels within 3–7 days. This profound testosterone-lowering effect was sustained throughout 4-week dosing periods. At those dose levels, the weights of the prostate and seminal vesicles were reduced to castrate levels. These suppressive effects of kisspeptin analogues were more rapid and profound than those induced by the GnRH agonist analogue leuprolide treatment. In addition, TAK-683 reduced plasma prostate specific antigen (PSA) in the JDCaP androgen-dependent prostate cancer rat model. Thus, chronic administration of kisspeptin analogues may hold promise as a novel therapeutic approach for suppressing reproductive functions and hormone-related diseases such as prostate cancer. Further studies are warranted to elucidate clinical significance of TAK-448 and TAK-683.

Is embryo quality superior when triggering of ovulation occurs by the administration of GnRH agonist analog over conventional hCG to trigger ovulation?

Is embryo quality superior when triggering of ovulation occurs by the administration of GnRH agonist analog over conventional hCG to trigger ovulation?

Aspiration and ethanol sclerotherapy to treat recurrent ovarian endometriomas prior to in vitro fertilization - a pilot study.

To describe the evolution of controlled ovarian hyperstimulation in women with recurrent ovarian endometriomas treated with sclerotherapy. Twenty-one patients with a laparoscopic diagnosis of stage III or IV endometriosis who had an endometrioma larger than 3 cm before ovarian hyperstimulation for in vitro fertilization were included in the study. After using a GnRH agonist analog for at least 20 days, the cysts were punctured using ultrasound guidance and subsequent ethanol sclerotherapy was performed. Then, the patients were stimulated with 100 or 200 U/day of recombinant follicle stimulating hormone, varying the dose according to the patient's age or history of a previous unilateral oophorectomy. The ovarian cysts had an average diameter of 4.7 ± 1.4 cm and did not recur after aspiration during the ovulation induction. Oocyte extraction occurred after 11 days of hyperstimulation, with 3.95 ± 3.30 oocytes obtained per cycle, on average. Embryo transfer occurred in 71.4% (15/21) of patients, and the pregnancy rate after transfer was 20% (3/15). Aspiration followed by ethanol sclerotherapy prior to in vitro fertilization can be an option for patients who desire a pregnancy and have recurrent endometriomas.

Leuprorelin acetate affects adhesion molecule expression in human prostate cancer cells

Reduced cell-cell adhesion allows malignant epithelial cells to invade the basal membrane and penetrate the stroma. This implies the potential of the cells to escape from the primary tumor as well as spreading ability. Herein, we investigated the effects of leuprorelin acetate (LA), a GnRH agonistic analogue, alone or in combination with dihydrotestosterone (DHT), on the expression of molecules involved in cell adhesion (E-cadherin, N-cadherin, α-, β- and γ-catenin) or in migration/invasion (c-met, CD44v6 and caveolin-1) in androgen-sensitive (LNCaP) and -insensitive (PC-3) prostate cancer (CaP) cells. We demonstrated by immunoblotting that, in LNCaP cells, molecules present in the adherens junctions (E-cadherin, α-, β- and γ-catenin) were expressed, while α-catenin was absent in PC-3 cells which expressed N-cadherin and c-met. In LNCaP cells, no changes in E-cadherin levels were produced by 10(-9) M DHT while LA (10(-11) or 10(-6) M) up-regulated the protein level (up to 26-30% after 48 h). In the same cells, β- and γ-catenin expression was enhanced either by DHT (24 and 20%, respectively) or LA (up to 18 and 40%, respectively), while α-catenin was not affected. Antagonistic effects were consistently observed between DHT and LA when the two hormones were jointly administered to the cells. Consistent results were obtained by immunocytochemistry. Co-immunoprecipitation analysis, used to verify the integrity of the LNCaP cell adhesion complex, demonstrated the association of E-cadherin with catenins. In PC-3 cells, adhesion molecule expression, analyzed by immunoblotting, was unaffected by LA, while a down-regulation of c-met (up to 28%) was observed after 24 h of treatment but which did not hold up over time (48-144 h). Our findings demonstrate the efficacy of LA in upregulating E-cadherin, β- and γ-catenin in LNCaP cells. This effect, that may be considered as another aspect of the direct antitumor activity of the GnRH analogue in hormone-dependent CaP cells, may contribute to maintenance/restoration of the normal tissue architecture counteracting the tumor cell spreading tendency.

Emerging gonadotropin-releasing hormone agonists

Introduction: Gonadotropin-releasing hormone agonist analogs (GnRHa) are peptides that mimic the action of gonadotropin-releasing hormone (GnRH) and are used to suppress subsequent sex steroid production. Although the analogs are a rather defined group of drugs, there have been developments in the past decades and there is still ample room for improvement. New therapeutic strategies in the use of GnRHs are discussed.Areas covered: Major points of discussion include: i) the use of concomitant treatment of early breast cancer in premenopausal estrogen-positive and -negative patients, ii) the use of GnRHa for fertility preservation in young female patients with malignant diseases and iii) the use of GnRH analogs in assisted reproduction. The manuscript provides a better understanding of GnRH agonists as well as an explanation of their major indications, biochemical pathways and concluding therapeutic strategies. Recent results from international meetings and debates are described to explain current controversies.Expert opinion: This paper highlights the need for more complex GnRH analogs. In the next few years, there will be longer acting GnRHas that may improve adherence. New therapeutic targets in oncological concepts may go beyond fertility preservation and focus on the antiproliferative effects of GnRH analogs.

Allopregnanolone levels decrease after gonadotropin-releasing hormone analog stimulation test in girls with central precocious puberty

Allopregnanolone, a neuroactive steroid mainly secreted by adrenals and gonads, is a hormone that seems to play a role in precocious puberty, as demonstrated by its high baseline levels found in girls with central precocious puberty (CPP). Allopregnanolone concentrations significantly increase after GnRH and ACTH stimulation test suggesting both its ovarian and adrenal production. Aim of this study was to evaluate allopregnanolone concentrations after GnRH and GnRH agonist analog stimulation test in girls with CPP to better establish its secretion source. Gonadotropins and steroid hormones were evaluated in different days after GnRH and triptorelin stimulation test in 15 CPP girls. After GnRH stimulation, LH, FSH, and allopregnanolone concentrations significantly increased (p<0.05). After triptorelin administration LH, FSH, estradiol and DHEAS levels significantly increased (p<0.05), while allopregnanolone concentrations significantly decreased (1.08±0.24 vs 0.87±0.28 nmol/l; p=0.003). The different response of allopregnanolone to GnRH and GnRH agonist analog might reflect the agonist and antagonist action exerted by these secretagogues. Our data suggest the prevalent gonadal allopregnanolone production in CPP subjects and the usefulness of its measurement in the diagnosis of CPP.

Luteal GnRH agonist prevents corpus luteum rescue in ovulation induction after use of menstrual HCG

OBJECTIVE: The use of a single recombinant hCG (rhCG) injection in the early follicular phase (EFP) to reduce secondary follicle cohort in high ovulatory responders has the drawback of rescuing previous corpus luteum (rCL). Resulting elevated progesterone (P4) in EFP is associated with lower pregnancy rate (PR) after IVF. Thus, we sought to evaluate whether: 1) late luteal phase (LLP) use of a long acting GnRH agonist analog (GnRHa) could prevent rCL caused by EFP rhCG administration; and 2) this tactic would improve IVF outcome.

Gonadotropin-releasing hormone agonist decreases chemotherapy-induced gonadotoxicity and premature ovarian failure in young female patients with Hodgkin lymphoma

To minimize the gonadotoxic effect of chemotherapy by the cotreatment with a GnRH agonistic analogue (GnRH-a). Prospective nonrandomized study with concurrent and historical controls. University medical center. One hundred fifteen female patients with Hodgkin lymphoma (HL). Sixty-five patients received a monthly injection of GnRH-a, administered before starting chemotherapy until its conclusion, up to a maximum of 6 months. Thirty-five patients were treated with ABVD and 76 with a procarbazine-containing regimen. This group was compared with a control group of 46 women who were treated concurrently with similar chemotherapy (n = 26) without GnRH-a or were historical controls (n = 20). Cyclic ovarian function (COF) versus premature ovarian failure (POF). The ovarian function could be determined in 111 patients. In the GnRH-a/chemotherapy group, 63 out of 65 patients resumed ovulation and regular menses (96.9 %), compared with 63% of the 46 control subjects. Twenty of the 22 patients in the BEACOPP/escalated BEACOPP/GnRH-a cotreatment resumed cyclic ovarian function versus 9 of the 14 in the chemotherapy-only group. All 17 MOPP/ABV/GnRH-a cotreated patients resumed COF versus 11 of the 22 in the chemotherapy-only group. There was no significant effect of the GnRH-a cotreatment regarding COF in the ABVD group. There were no significant differences in the cumulative doses of the various alkylating agents between the two groups. Cotreatment with GnRH-a may reduce ovarian damage significantly in female patients treated for HL and should be considered in addition to assisted reproduction for women in reproductive age receiving gonadotoxic chemotherapy.

A randomised controlled study of goserelin as adjunctive therapy prior to surgery in the management of uterine fibroids

Context : Luteinising hormone analogues are being increasingly advocated in the management of common oestrogendependent gynaecological conditions, notably uterine fibroids, endometriosis and menorrhagia. Objective : The aim was to assess the effects of depot injections of goserelin (Zoladex ® ), a GnRH-agonist analogue, on the management of uterine fibroids. Patients and Methods : Forty female pre-menopausal patients aged between 26 and 50 years, with uterine sizes 12 to 26 weeks were enrolled in a randomised controlled study. One group was prospectively randomized to surgery (deferred for 0 to 4 months) and another to goserelin treatment for 3 months, followed by surgery. Patients were included if they had a diagnosis of benign uterine fibroids and an abdomino-pelvic mass greater than 12 weeks gestational size. Results : Uterine and fibroids volumes were reduced by a median value of 31.7% and 58.1% respectively for Zoladex patients compared with an increase of 3.3% and 0.6% in uterine and fibroid volumes in the surgery-only patients. The difference between the treatment groups for the absolute changes was statistically significant (P Conclusion : Goserelin treatment, prior to surgery, demonstrated benefit in terms of uterine and fibroids volumes, symptoms reduction and improvement of haematological profile in Nigerian patients with uterine leiomyoma. Keywords : uterine fibroids, goserelin, adjunctive therapy, surgery Tropical Journal of Obstetrics and Gynaecology Vol. 22(2) 2005: 120-124

Análogo de GnRH disminuye la secreción de hormona folículo estimulante (FSH) en ovejas prepúberes

SUMMARY LH and FSH secretions depend on the pulsatile secretion of GnRH from the hypothalamus. However, the grade of dependency as well as the relationship between pulses of GnRH and pulses of FSH secretion is less clear. Experiments in monkeys have shown that high GnRH pulse frequency favors LH secretion while low frequency of GnRH pulses preferentially stimulates the FSH secretion. The objective of the present work was to recognize the dependence of GnRH on the FSH secretion in prepubertal female sheep. A GnRH agonist analogue in slow release microcapsule preparation was used (Trp6-GnRH, (Decapeptyl®)) whose blocking effect on the LH release has been previously demonstrated. The analogue was injected intramuscularly every 4 weeks beginning at 20 weeks of age three times in five Suffolk ewe lambs. Another group of five lambs received the vehicle of Decapeptyl. Studies of FSH pulsatility were carried out at 20 (before the analogue agonist administration), 26 and 30 weeks of age. The CLUSTER program was used to identify characteristics of FSH secretion: transversal mean (ng/ml/5h), frequency of pulses (number of pulses/5h), amplitude of pulses (ng/ml) and nadir (ng/ml) . In the control group, FSH secretion characteristics did not change between 20 and 30 weeks of age. In the experimental group, mean FSH concentrations decreased from 3.4±0.3 ng/ml/5h at 20 weeks of age to 0.36 ±0.1 ng/mL/ 5h at 30 weeks of age (P<0,05), which was also significantly lower than in the control group of the same age. Amplitude of FSH pulses in lambs of 30 weeks of age were significantly lower than in lambs of 20 weeks of age (4.4 ± 0.5 versus 0.5 ± 0.1 ng/mL respectively, P<0.05), and lower than that exhibited by control ewe lambs of 30 weeks of age. FSH pulse frequency did not change between lambs of 20 and 30 weeks of age in either group. Results show that the GnRH analogue is able to block the FSH secretion suggesting that the FSH secretion is dependant on GnRH stimulation in prepubertal female sheep.

Preservation of Fertility and Ovarian Function and Minimization of Chemotherapy-Induced Gonadotoxicity in Young Women by GnRH-a

Improved long-term survival in young women with lymphoma and leukemia has increased attention to the preservation of their future fertility. We have attempted to minimize the gonadotoxic effect of chemotherapy by cotreatment with a GnRH agonist analog, inducing a temporary prepubertal milieu. Our prospective clinical case series includes 92 women with lymphoma, aged 15-40 years, 10 with leukemia and 18 undergoing chemotherapeutic treatments for nonmalignant autoimmune diseases. Depot D-TRP6-GnRH-a was injected monthly from before the initiation of chemotherapy until its conclusion, for up to 6 months. We used 82 similarly treated patients with lymphoma not given GnRH-a as a comparison group. All but five of the surviving evaluable patients with GnRH-a/chemotherapy cotreatment resumed spontaneous ovulation and menses or conceived, whereas 53% of the patients in the comparison group experienced premature ovarian failure (P<.01). Mechanisms to explain this apparent chemoprotective effect are discussed, and the work of other investigators in this area is reviewed.

Clinical pharmacokinetics of depot leuprorelin.

Leuprorelin acetate is a synthetic agonist analogue of gonadotropin-releasing hormone. Continued leuprorelin administration results in suppression of gonadal steroid synthesis, resulting in pharmacological castration. Since leuprorelin is a peptide, it is orally inactive and generally given subcutaneously or intramuscularly. Sustained release parenteral depot formulations, in which the hydrophilic leuprorelin is entrapped in biodegradable highly lipophilic synthetic polymer microspheres, have been developed to avoid daily injections. The peptide drug is released from these depot formulations at a functionally constant daily rate for 1, 3 or 4 months, depending on the polymer type [polylactic/glycolic acid (PLGA) for a 1-month depot and polylactic acid (PLA) for depot of >2 months], with doses ranging between 3.75 and 30mg. Mean peak plasma leuprorelin concentrations (C(max)) of 13.1, 20.8 to 21.8, 47.4, 54.5 and 53 microg/L occur within 1 to 3 hours of depot subcutaneous administration of 3.75, 7.5, 11.25, 15 and 30 mg, respectively, compared with 32 to 35 microg/L at 36 to 60 min after a subcutaneous injection of 1mg of a non-depot formulation. Sustained drug release from the PLGA microspheres maintains plasma concentrations between 0.4 and 1.4 microg/L over 28 days after single 3.75, 7.5 or 15mg depot injections. Mean areas under the concentration-time curve (AUCs) are similar for subcutaneous or intravenous injection of short-acting leuprorelin 1mg; a significant dose-related increase in the AUC from 0 to 35 days is noted after depot injection of leuprorelin 3.75, 7.5 and 15mg. Mean volume of distribution of leuprorelin is 37L after a single subcutaneous injection of 1mg, and 36, 33 and 27L after depot administration of 3.75, 7.5 and 15mg, respectively. Total body clearance is 9.1 L/h and elimination half-life 3.6 hours after a subcutaneous 1mg injection; corresponding values after intravenous injection are 8.3 L/h and 2.9 hours. A 3-month depot PLA formulation of leuprorelin acetate 11.25mg ensures a C(max) of around 20 microg/L at 3 hours after subcutaneous injection, and continuous drug concentrations of 0.43 to 0.19 microg/L from day 7 until before the next injection. Recently, an implant that delivers leuprorelin for 1 year has been evaluated. Serum leuprorelin concentrations remained at a steady mean of 0.93 microg/L until week 52, suggesting zero-order drug release from the implant. In general, regular or depot leuprorelin treatment is well tolerated. Local reactions are more common after application of the 3- or 4-month depot in comparison with the 1-month depot.

Preservation of fertility and ovarian function and minimalization of chemotherapy associated gonadotoxicity and premature ovarian failure: the role of inhibin-A and -B as markers

Background: Following the improved long term survival in young women with lymphoma and leukemia undergoing chemotherapy, the preservation of future fertility has been the focus of recent interest. The investigational endeavors of ovarian cryopreservation awaits the clinical experience of in-vitro maturation of thawed primordial follicles, their in-vitro fertilization and ET. Although promising, this experience is not available yet. Moreover, the risk of possible reimplantation of malignant stem cells with the thawed cryoperserved ovary has been raised, following experimental animal observations. Therefore, until these innovative endeavors prove successful, and in parallel to them we attempted to minimize the gonadotoxic effect of chemotherapy by the co-treatment with a GnRH agonistic analogue to induce a temporary prepubertal milieu. Whereas, inhibin-B concentrations in serum may reflect the ovarian granulosa cell compartment, inhibin-A reflects luteal function. The immunoreactive inhibin-A and -B in these patients, before, during, and following the gonadotoxic chemotherapy were measured. Methods: A prospective clinical protocol was undertaken in 55 women with lymphoma, aged 15–40 years, ten with leukemia and eight undergoing chemotherapeutic treatments for non malignant diseases such as systemic lupus erythematosus (SLE) or other autoimmune diseases. A monthly injection of depot D-TRP6-GnRH-a was administered from before starting the chemotherapy until its conclusion, up to a maximum of 6 months. Hormonal profile (FSH, LH, E2, T, P4, IGF-1, IGF-BP3, and PRL) was taken before starting the GnRH-a/chemotherapy co-treatment, and monthly thereafter, until resuming spontaneous ovulation. This group was compared with a control group of 55 women who have been treated with similar chemotherapy. Inhibin-A and -B immunoactivity was measured by an ELISA commercial kit (Serotec). Results: Whereas, all but three (40- and 36-year-old) of the surviving patients with GnRH-a/chemotherapy co-treatment group resumed spontaneous ovulation and menses within 12 months, less than half of the patients in the control group (chemotherapy without GnRH-a co-treatment) resumed ovarian function and regular cyclic activity ( P<0.05). The remaining 56% experienced premature ovarian failure (POF). Temporary increased FSH concentrations were experienced by about a third of the patients resuming cyclic ovarian function, suggesting a reversible ovarian damage in a larger proportion of women than those experiencing POF. Inhibin-A and -B decreased during the GnRH-a/chemotherapy co-treatment but increased to normal levels in patients who resumed regular ovarian cyclicity, and/or spontaneously conceived, as compared with low levels in those who developed POF. Conclusions: If these preliminary data are consistent in a larger group of patients, inhibin-A or -B concentrations may serve as prognostic factors for predicting the resumption of ovarian function, in addition to the levels of FSH, LH and E2. The GnRH-a co-treatment should be considered in every woman in the reproductive age receiving chemotherapy, in addition to ART, and to the investigational attempts of ovarian cryopreservation for future in-vitro maturation, autotransplantation, or xenotransplantation.

Follicle-stimulating hormone or human menopausal gonadotropin for ovarian stimulation in in vitro fertilization cycles: a meta-analysis

Objective: To reanalyze the results of using FSH alone and hMG during IVF treatment, taking into account the different protocols of administration of superactive GnRH agonist analogs. Design: Meta-analysis. Setting: The London Women’s Clinic. Patient(s): Women undergoing IVF treatment. Intervention(s): A meta-analysis of published randomized controlled trials from 1985 to 1999 of the use of FSH versus hMG for ovarian stimulation during IVF treatment. The common Peto odds ratio was calculated with use of a fixed effect model. The overall log odds ratio was estimated after demonstrating the consistency or homogeneity of the study results. Main Outcome Measure(s): Clinical pregnancy rate per cycle of IVF. Result(s): The results suggested that in the “long and short GnRH agonists protocol” of IVF, FSH, and hMG were equally effective in achieving ovarian stimulation, and there were no differences in the clinical pregnancy rates per cycle of IVF. However, in protocols where no pituitary desensitization was used, FSH alone was more efficacious. Conclusion(s): The optimum choice of gonadotropin preparation for ovarian stimulation during IVF treatment is influenced by the regimen of pituitary desensitization used. The optimum gonadotropin to be used when GnRH antagonists are used has yet to be determined.

Preservation of fertility and ovarian function and minimizing chemotherapy-induced gonadotoxicity in young women.

After the improved long-term survival in young women with lymphoma and leukemia undergoing chemotherapy, the preservation of future fertility has been the focus of recent interest. Three major topics are reviewed. They include the following: (1) the role of chemotherapy in the treatment of malignant and nonmalignant disease in young women, the types of chemotherapy and their gonadal effects (differing between ovaries and testes) in both human and other species, and the reasons for differences in the outcomes of various studies; (2) the human experience with GnRH-agonist therapy for minimizing chemotherapy-associated gonadotoxicity; and (3) inhibin measurements in young women treated by chemotherapy and in perimenopausal patients and those with impending premature ovarian failure (POF). Whereas egg retrieval for in vitro fertilization (IVF) and embryo cryopreservation is a valid assisted reproductive technology (ART) for married couples, it may be unacceptable for the young single woman. The investigational endeavors of ovarian cryopreservation awaits the clinical experience of in vitro maturation of thawed primordial follicles, their IVF, and embryo transfer. Although promising, this experience is not yet available. Moreover, the risk of possible reimplantation of malignant stem cells with the thawed cryopreserved ovary has been raised after animal observations. Therefore, until these innovative endeavors prove successful, and in parallel with them, an attempt was made to minimize the gonadotoxic effect of chemotherapy by the cotreatment with a GnRH agonistic analogue (GnRH-a) to induce a temporary prepubertal milieu, because prepubertal ovaries were found more resistant to alkylating agents' effect than the ovaries of older women. To characterize the correlation with ovarian function after gonadotoxic chemotherapy for Hodgkin or non-Hodgkin lymphoma in young women, the immunoreactive inhibin-A concentrations in the sera of these patients were measured before, during, and after the gonadotoxic chemotherapy. The GnRH-a cotreatment should be considered in every woman in the reproductive age receiving chemotherapy, in addition to ART and the investigational attempts of ovarian cryopreservation for future in vitro maturation or reimplantation. If these preliminary data are confirmed in a larger group of patients, inhibin-A concentrations may serve as a prognostic factor for predicting the resumption of ovarian function in addition to the levels of FSH, LH, and estradiol.