leuprolide and Primary-Ovarian-Insufficiency

Administration of cyclophosphamide (CYC), an alkylating agent used to treat malignancies and severe rheumatic diseases, creates a risk of ovarian insufficiency that is related to the intensity and duration of therapy and the age of the patient. To preserve reproductive capacity in the appropriate clinical setting, oocyte, embryo, and/or ovarian tissue cryopreservation are recommended. Medical protection with depot gonadotropin-releasing hormone agonists (GNRHa) has emerged as a potential means to preserve both fertility and ovarian function through the suppression of ovarian activity during treatment with alkylators. We review the trials of GNRHa for ovarian protection in both cancer and rheumatic disease patients. Trials in cancer patients receiving CYC alone, or in combination with other gonadotoxic agents that have employed several different GNRHa have yielded mixed results. Trials in lupus patients receiving lower doses of CYC alone utilizing depot leuprolide acetate have tended to show favorable results.

Topics: Alkylating Agents; Cyclophosphamide; Female; Fertility Agents, Female; Gonadotropin-Releasing Hormone; Humans; Immunosuppressive Agents; Leuprolide; Lupus Erythematosus, Systemic; Primary Ovarian Insufficiency

Topics: Animals; Antineoplastic Agents; Camptothecin; Female; Freezing; Gonadotropin-Releasing Hormone; Humans; Infertility, Female; Irinotecan; Leuprolide; Organ Preservation; Ovary; Primary Ovarian Insufficiency

In the randomised phase II LEO trial, we investigated the effect of adding everolimus (EVE) to letrozole (LET) in ovarian-suppressed premenopausal women with hormone receptor-positive (HR+), HER2-negative (HER2-) recurrent/metastatic breast cancer.. Patients with progression or prior exposure to tamoxifen with or without gonadotropin-releasing hormone agonists, either sequentially or concurrently, in adjuvant or metastatic setting were randomly assigned (2:1) to the EVE arm (leuprorelin + LET + EVE) or the LET arm (leuprorelin + LET) until disease progression or unacceptable toxicity. The primary end-point was progression-free survival (PFS). Secondary end-points included overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR) and safety.. Between January 2014 and October 2018, 137 patients were enrolled (median age, 44 years [range, 24-56]). Of them, 75% had endocrine-sensitive disease, and 61% had visceral metastasis. With the median follow-up of 32.4 months, the median PFS was 18.1 months in the EVE arm and 13.8 months in the LET arm (HR 0.73, P = 0.137). Among patients with visceral metastases, the median PFS was significantly longer in the EVE arm (16.4 versus 9.5 months, P = 0.048). The median OS was not reached in both arms. The CBR was significantly higher in the EVE arm (83% versus 62%, P = 0.010). The ORR was similar between the two arms. The most common grade 3/4 adverse events in the EVE arm were neutropenia, alanine aminotransferase elevation and anaemia.. EVE plus LET with ovarian-suppression resulted in longer PFS in tamoxifen-exposed HR+, HER2- metastatic breast cancer patients with visceral metastasis.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Everolimus; Female; Follow-Up Studies; Gonadotropin-Releasing Hormone; Humans; Letrozole; Leuprolide; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Premenopause; Primary Ovarian Insufficiency; Prognosis; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; Survival Rate; Tamoxifen; Young Adult

Premature ovarian failure occurs in 40%-70% of patients who receive conventional chemotherapy alone. However, the incidence is higher, 70%-100%, in patients who undergo myeloablative chemotherapy with hematopoietic stem cell transplantation (HSCT). Gonadotropin-releasing hormone (GnRH) analogs, such as leuprolide, in a continuous-release formulation, may protect the ovaries from the gonadotoxic effects of chemotherapy. In non-HSCT settings, GnRH analogs have reduced the risk for premature ovarian failure to <10%. We conducted a phase II clinical trial based on the hypothesis that giving leuprolide before conditioning chemotherapy in HSCT patients reduces premature ovarian failure incidence.. Eligible patients were women aged ≤40 years who were HSCT candidates, were premenopausal, and had both follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels ≤20 IU/L. Two 22.5-mg leuprolide doses were delivered in 3-month depot i.m. injections, the first within 2 months before HSCT. Patients were monitored for menstruation return, and ovarian function tests (FSH, LH, and estradiol) were done every 2 months starting 90 days after the last leuprolide dose.. Sixty eligible patients were enrolled, 59 underwent HSCT, and 44 were evaluable (median age, 25 years; median follow-up, 355 days). Only seven of 44 patients (16%) regained ovarian function. Of the 33 who received myeloablative regimens, six (18%) regained ovarian function. However, among the 11 who received nonmyeloablative regimens, only one (9%) regained ovarian function (p = .66).. Leuprolide did not preserve ovarian function in patients who underwent HSCT using either myeloablative or nonmyeloablative regimens. Other measures that protect ovarian function need to be investigated.

Topics: Adolescent; Adult; Female; Hematopoietic Stem Cell Transplantation; Humans; Leuprolide; Ovary; Primary Ovarian Insufficiency

The increased survival of patients with breast cancer has given rise to other problems associated with the complications of chemotherapy. One major complication is premature ovarian failure, an especially harmful outcome for women of reproductive age. This study was performed to evaluate the efficacy of GnRH agonist (GnRHa) treatment on protecting ovarian function in young breast cancer patients (30.59+/-5.1 yr) receiving chemotherapy after surgery. Twenty-two women were enrolled and given subcutaneous injections of leuprolide acetate (3.75 mg) every 4 weeks during chemotherapy. Follow-up laboratory tests (luteinizing hormone [LH], follicle stimulating hormone [FSH], and estradiol) were performed 1, 3, and 6 months after chemotherapy. Menstruation patterns and clinical symptoms were followed up for a mean duration of 35.6+/-1.7 months. FSH and LH levels were normal in all patients 6 months after completing chemotherapy (8.0+/-5.3, 4.4+/-2.7 mIU/mL, respectively). During follow-up, none of the patients complained of menopausal symptoms and 81.8% experienced recovery of menstruation. This report is the first trial of GnRHa as a treatment modality to protect ovarian function during adjuvant chemotherapy in young Korean breast cancer patients.

Topics: Adult; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Breast Neoplasms; Combined Modality Therapy; Cyclophosphamide; Doxorubicin; Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Luteinizing Hormone; Menstruation; Ovarian Function Tests; Primary Ovarian Insufficiency; Republic of Korea; Tamoxifen; Time Factors

The aim of this study was to evaluate the protective effect of concomitant leuprolide treatment on ovarian function in young women undergoing adjuvant chemotherapy for early breast cancer. 19 women, median age 36.5 years (range 26-40 years), with operable breast cancer and negative hormonal receptors, received six cycles of FEC 100 regimen as adjuvant chemotherapy and co-treatment with leuprolide. Menstrual resumption was gained in all patients in a median time of 5 months (range 3-8). Follicle-stimulating hormone and estradiol assessment was performed in all patients. The return to pre-menopausal values was achieved within 6 months of the last leuprolide administration. At a median follow-up of 3 years (range 1-5 years), no patient relapsed and four full-term pregnancies were recorded in four women, each of whom delivered a healthy infant. Our data are in agreement with similar experiences and confirm the activity of GnRH therapy in preventing ovarian failure.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Chemotherapy, Adjuvant; Estradiol; Female; Fertility Agents, Female; Follicle Stimulating Hormone; Humans; Leuprolide; Pregnancy; Pregnancy Rate; Primary Ovarian Insufficiency

Cyclophosphamide (CYC) therapy for systemic lupus erythematosus (SLE), a disease predominantly affecting women of childbearing age, causes an unacceptably high incidence of irreversible premature ovarian failure (POF). This study was performed to evaluate the effectiveness of depot leuprolide acetate, a synthetic gonadotropin-releasing hormone analog (GnRH-a), for protection against POF during CYC therapy.. Young women with severe SLE treated in a standardized protocol of monthly intravenous bolus CYC were offered treatment with GnRH-a (depot leuprolide acetate; a 3.75-mg monthly injection during the standard CYC regimen). Patients treated with GnRH-a were compared with controls individually matched by age (+/-5 years) and by cumulative CYC dose (+/-5 gm). Reproductive status was determined after a minimum followup of 3 years after CYC therapy. The primary outcome was time to POF. Paired summary statistical analyses, Kaplan-Meier survival estimates, and Cox regression analyses were performed to assess differences in outcome between groups.. POF developed in 1 of 20 women treated with GnRH-a (5%) compared with 6 of 20 controls (30%) matched by age and cumulative CYC dose (matched odds ratio 0.09, P < 0.05). Kaplan-Meier estimates demonstrated improved cumulative ovarian protection over time in the GnRH-a-treated group (P = 0.04).. Treatment with GnRH-a during CYC therapy was associated with a significant reduction of POF in young women with severe SLE.

Topics: Adult; Cyclophosphamide; Data Interpretation, Statistical; Female; Fertility Agents, Female; Follicle Stimulating Hormone; Humans; Immunosuppressive Agents; Leuprolide; Lupus Erythematosus, Systemic; Ovary; Primary Ovarian Insufficiency; Survival Analysis; Treatment Outcome

To determine the effect of leuprolide acetate, a synthetic gonadotropin-releasing hormone analog (GnRH-a) on ovarian function preservation in systemic lupus erythematosus (SLE) patients treated with cyclophosphamide (CYC) in clinical practice.. We enrolled 30 premenopausal female SLE patients who fulfilled the 1997 American College of Rheumatology revised criteria and were treated with intravenous CYC (IVCY) in 2008-2017. We used Kaplan-Meier survival estimates to compare the GnRH-a-treated patients and those not treated with GnRH-a as controls. We performed Cox regression analyses to identify factors associated with premature ovarian failure (POF), incidences of cardiovascular events, strokes and osteoporosis after IVCY therapy.. After a mean follow-up of 41 months, POF developed in one of the 16 GnRH-a-treated patients (6%) versus seven of the 14 controls (50%). Significantly improved cumulative ovarian protection over time was observed in the GnRH-a-treated group (P = 0.030). The hazard model analysis showed that treatment with GnRH-a during IVCY therapy is an independent factor associated with POF after IVCY therapy (adjusted hazards ratio = 0.12, 95% CI 0.01-0.67, P = 0.013) but not incidences of cardiovascular events, strokes or osteoporosis.. The combined use of GnRH-a with IVCY therapy was associated with a significant reduction of POF among premenopausal women with SLE, suggesting that the addition of GnRH-a can be a strategy to prevent POF among premenopausal women with SLE after IVCY therapy.

Topics: Administration, Intravenous; Adult; Cardiovascular Diseases; Case-Control Studies; Cyclophosphamide; Female; Fertility Agents, Female; Fertility Preservation; Humans; Immunosuppressive Agents; Incidence; Infertility, Female; Kaplan-Meier Estimate; Leuprolide; Lupus Erythematosus, Systemic; Multivariate Analysis; Osteoporosis; Ovary; Premenopause; Primary Ovarian Insufficiency; Proportional Hazards Models; Stroke; Time Factors; Treatment Outcome; Young Adult

Concurrent endocrine therapy with chemotherapy had a concern of potential antagonism. However, gonadotropin-releasing hormone (GnRH) agonist has been used concurrently with chemotherapy to prevent premature ovarian failure for young breast cancer patients. The aim of this study was to determine the impact of concurrent use of GnRH agonists on relapse-free and overall survival, and to establish the oncologic safety of ovarian protection with GnRH agonists.. Premenopausal women aged between 20 and 40 years who received adjuvant chemotherapy for breast cancer from January 2002 to April 2012 were classified into two groups; One treated with GnRH agonists for ovarian protection during chemotherapy, and the other without ovarian protection. A propensity score matching strategy was used to create matched sets of two groups with age, pathologic stage, hormone receptor, and Her2 status.. A total of 101 patients treated with concurrent GnRH agonist during chemotherapy were compared with 335 propensity score matched patients. Among them, 81.2% were younger than 35 years and 58.4% were hormone responsive. Survival analysis using stratified Cox regression showed that women treated with concurrent GnRH agonists had better recurrence-free survival (adjusted Hazard ratio 0.21, p = 0.009; unadjusted Hazard ratio 0.33, p = 0.034).. Ovarian protection using GnRH agonists can be safely considered for young women with breast cancer in terms of oncologic outcomes. Further studies are needed to assess the long-term outcomes of concurrent GnRH agonist use with chemotherapy.

Topics: Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Chemotherapy, Adjuvant; Female; Fertility Agents, Female; Goserelin; Humans; Leuprolide; Logistic Models; Mastectomy; Neoplasm Recurrence, Local; Primary Ovarian Insufficiency; Propensity Score; Retrospective Studies; Survival Analysis

We report the first case, to the best of our knowledge, of successful conception following ovarian induction in a patient with premature ovarian failure and undetectable serum anti-Müllerian hormone. A 34-year-old woman was referred because of ovarian amenorrhea. After endogenous gonadotrophins were normalized by hormone-replacement therapy and gonadotrophin-releasing hormone agonist, ovarian induction was performed using exogenous gonadotrophins. On ovarian induction day 8, one follicle had reached a mean diameter of 19.6 mm, the serum estradiol level had increased to 516 pg/mL, and human chorionic gonadotrophin (HCG) was injected. On HCG injection day 7, ultrasonography was unable to detect the follicle, and serum progesterone levels had increased to 6.1 ng/mL. One month after HCG injection, ultrasonography detected an intrauterine fetus with beating heart. Even with serum anti-Müllerian hormone levels below the threshold of detection, there is a chance for patients with premature ovarian failure.

Topics: Adult; Anti-Mullerian Hormone; Embryo Implantation; Estrogen Replacement Therapy; Female; Fertility Agents, Female; Gonadotropin-Releasing Hormone; Humans; Infertility, Female; Leuprolide; Menotropins; Ovulation Induction; Pregnancy; Primary Ovarian Insufficiency; Severity of Illness Index

Topics: Female; Hematopoietic Stem Cell Transplantation; Humans; Leuprolide; Ovary; Primary Ovarian Insufficiency

Topics: Adolescent; Adult; Antineoplastic Agents; Cryopreservation; Ethics, Clinical; Female; Fertility Agents, Female; Humans; Infertility, Female; Leuprolide; Medical Oncology; Neoplasms; Oocytes; Practice Guidelines as Topic; Primary Ovarian Insufficiency; Societies, Medical; Transplantation, Autologous; United States; Young Adult

Topics: Acute Disease; Adolescent; Adult; Antineoplastic Agents, Hormonal; Drug Evaluation; Female; Humans; Leukemia; Leuprolide; Menstruation; Ovulation; Primary Ovarian Insufficiency; Retrospective Studies

A 2-3 fold higher urinary pregnanediol glucuronide excretion has been observed in women with premature ovarian failure, compared with age-appropriate menopausal women. Progesterone, the precursor of urinary pregnanediol glucuronide, is a secretory product of either adrenal or ovarian origin. We postulated that suppression of pituitary gonadotrophin secretion by down-regulation with a long-acting gonadotrophin-releasing hormone agonist, leuprolide acetate, would decrease ovarian but not adrenal pregnanediol glucuronide. This would demonstrate a major difference in the ovarian hormonal milieu of these two groups of women. Four volunteers with premature ovarian failure collected daily first morning voided urine samples for 1 month prior to leuprolide acetate administration. Leuprolide acetate was then administered monthly for 3 months while continuing daily urinary collection. Luteinizing hormone (LH), follicle stimulating hormone (FSH), and pregnanediol glucuronide were measured in all samples and normalized for creatinine. Comparisons of pre- and post-median values for luteinizing hormone (LH), FSH, and pregnanediol glucuronide were made using the Wilcoxon rank sum test. This demonstrated significant suppression of both LH and FSH. Pregnanediol glucuronide, however, did not demonstrate a significant decline, strongly implying an adrenal source of the enhanced excretion. The decreased pregnanediol glucuronide noted in age-appropriate menopausal women compared with premature ovarian failure is likely to be a reflection of adrenal ageing.

Topics: Adrenal Glands; Adult; Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Luteinizing Hormone; Models, Biological; Ovary; Pregnanediol; Primary Ovarian Insufficiency

Topics: Buserelin; Contraceptives, Oral; Dexamethasone; Female; Fertilization in Vitro; Gonadotropin-Releasing Hormone; Goserelin; Growth Hormone; Growth Substances; Humans; Infertility, Female; Leuprolide; Oocyte Donation; Pregnancy; Primary Ovarian Insufficiency

Our purpose was to evaluate the effect of age on endometrial receptivity and to compare success rates for oocyte donation among groups with differing primary diagnoses.. This was a retrospective analysis of 300 consecutively attempted oocyte donation cycles.. The setting was the in vitro fertilization program at the University of Southern California.. Recipients were divided into groups according to age: Group I, < 30 years (n = 8); Group II, 30-39 years (n = 59); Group III, 40-49 years (n = 107); and Group IV, 50-59 years (n = 18). Additionally, indications for treatment were divided into Classes A-G according to a primary diagnosis given to each patient and included premature ovarian failure (n = 44), surgical castration (n = 9), genetic disease carrier (n = 12), transitional menopause (n = 27), natural menopause (n = 30), multiple IVF failures (n = 62), and postchemotherapy (n = 8). Recipients received oral micronized estradiol and intramuscular progesterone. Oocytes were donated by fertile young women utilizing ovarian hyperstimulation with menopausal gonadotropins.. There were no significant differences among groups or classes related to either the number of oocytes received or the number of embryos transferred per cycle. Rates for embryo implantation and resorption and the clinical and ongoing or delivered pregnancy rates were similarly not different among patients except for women who previously received chemotherapy, where a significantly elevated rate of spontaneous abortion was noted P < 0.05).. The establishment of pregnancy utilizing oocyte donation is not adversely affected by the chronological age of the recipient, inferring that the age-related decline in fertility is due primarily to oocyte aging, and not to loss of endometrial receptivity. Also, prior exposure to chemotherapy may alter endometrial integrity and lead to greater pregnancy wastage in women receiving donated embryos.

Topics: Abortion, Spontaneous; Administration, Oral; Adult; Age Factors; Antineoplastic Agents; California; Drug Administration Schedule; Embryo Implantation; Estradiol; Female; Fertilization in Vitro; Fetal Resorption; Genetic Diseases, Inborn; Humans; Infertility, Female; Injections, Intramuscular; Injections, Subcutaneous; Leuprolide; Maternal Age; Menopause; Menotropins; Middle Aged; Oocyte Donation; Ovariectomy; Pregnancy; Pregnancy, High-Risk; Primary Ovarian Insufficiency; Progesterone; Retrospective Studies; Universities

Previous data have suggested there is a higher incidence of luteinized unruptured follicle (LUF) syndrome (defined as failure to release any oocyte as determined by sonography) in gonadotropin-treated patients following human chorionic gonadotropin (hCG) versus the gonadotropin releasing hormone agonist (GnRH-a) leuprolide acetate. The present study was designed to determine if an ultra low-dose gonadotropin regimen, designed not to raise the serum estradiol level much above normal for non-stimulated cycles, might result in a decrease in LUF following hCG treatment, and even reduce the rate to that seen following leuprolide acetate. The hypothesis tested was that the higher estradiol levels might suppress the pre-ovulatory follicle stimulating hormone (FSH) surge which, in turn, would inhibit plasmin production, thus preventing detachment of the oocyte from the follicle. The data did show a reduced rate of LUF incidence with either hCG or leuprolide acetate in ultra low-dose human menopausal gonadotropin-(hMG-) treated patients compared to data from previous studies with conventional hMG/hCG therapy. Pregnancy rates were also similar following hCG or leuprolide acetate for release in low-dose hMG-treated patients. Preliminary data show that leuprolide acetate is superior to hCG for causing oocyte release when stimulation is with low-dose purified FSH, and possibly also that low-dose hMG is superior to low-dose purified FSH for producing superior pregnancy rates.

Topics: Adult; Chorionic Gonadotropin; Estradiol; Female; Follicle Stimulating Hormone; Humans; Leuprolide; Luteal Phase; Luteinizing Hormone; Menotropins; Ovulation Induction; Pregnancy; Primary Ovarian Insufficiency; Progesterone

We compared serum concentrations of immunoreactive inhibin, hCG, and FSH in normal women with those of two groups of women lacking endogenous luteal function. Twelve functionally agonadal, hypergonadotropic women with premature ovarian failure were given replacement ovarian steroids. Donor oocytes were fertilized in vitro with the husband's semen, and embryos were transferred into these women. A second group of 12 women were normogonadotropic but anovulatory, had undergone previously unsuccessful in vitro fertilization, and possessed cryopreserved embryos. These women were suppressed with a GnRH agonist before sex hormone replacement. Serum samples collected at weeks 2, 3, 4-6, 8-10, and 12-14 of pregnancy were measured for FSH, hCG, and immunoreactive inhibin. Data were compared with concentrations in normally ovulating women with well-established dates of conception. Sex steroid replacement hormone levels did not differ between the ovarian-failure and agonist-suppressed women and approximated that of normal cycles until pregnancy; thereafter, estradiol and progesterone levels remained higher than normal. Despite excessive steroid replacement, FSH remained higher in women with ovarian failure than in agonist-suppressed or normal women. On immunoassay, inhibin failed to show an early rise at 4-6 weeks of pregnancy in either group of aluteal women (0.52 +/- 0.05 ng/mL), whereas normal women demonstrated 0.9 +/- 0.05 ng/mL inhibin in their sera (P less than .001). By 8-10 weeks of pregnancy, women with ovarian failure demonstrated inhibin concentrations identical to those of normal women (1.2 +/- 0.1 and 1.2 +/- 0.15 ng/mL, respectively), whereas agonist-suppressed women lagged behind (0.7 +/- 0.1 ng/mL) (P less than .02).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Chorionic Gonadotropin; Corpus Luteum; Embryo Transfer; Estradiol; Estrogen Replacement Therapy; Female; Fertilization in Vitro; Follicle Stimulating Hormone; Humans; Inhibins; Leuprolide; Pregnancy; Primary Ovarian Insufficiency; Progesterone