Effect of Parquetina nigrescens (Afzel.) Leaves on Letrozole-Induced PCOS in Rats: a Molecular Insight into Its Phytoconstituents.

Polycystic ovarian syndrome (PCOS) is one of the common causes of female infertility in women of reproductive age. P. nigrescens is a plant used in the treatment of various diseases including menstrual disorders. This study investigated the effect of ethanolic extracts of P. nigrescens leaves on the estrous cycle, fasting blood glucose, and hormonal and lipid profile in letrozole-induced PCOS rats and also evaluated the molecular mechanism of the active constituents using computational methods. After the induction of PCOS with letrozole, rats were treated orally for 14 days with distilled water (1 mg/kg/day), clomiphene citrate (2 mg/kg/day), metformin (7.14 mg/kg/day), and ethanolic extract of P. nigrescens (50 and 100 mg). Thereafter, selected biochemical parameters were assayed to determine the extract's effect on the estrous cycle. Molecular docking and molecular dynamics simulation (MDS) were carried out to determine the binding affinity and relative stability of the ligand-receptor complexes. Letrozole-induced PCOS rats showed irregular estrous cyclicity, elevated (p > 0.05) triglycerides, low-density lipoprotein cholesterol (LDL), total cholesterol, insulin, testosterone, and luteinizing hormone (LH) concentration, low (p > 0.05) progesterone, low follicle-stimulating hormone (FSH), high-density lipoprotein cholesterol (HDL), and high fasting blood glucose concentration compared to that of the control group. The reproductive, biochemical, and structural alterations were reversed by the administration of ethanolic extract of P. nigrescens leaves (50 mg/kg) which restored the estrous cycle after 14 days of treatment. However, the ethanolic extracts of P. nigrescens (100 mg/kg) significantly increased (p > 0.05) FSH, HDL, and progesterone concentrations but decreased the LH, progesterone, and total cholesterol. Of all 44 compounds identified in GCMS analysis of an ethanolic extract of P. nigrescens leaves, only 2-ethylbutyl heptyl ester (CID 91705405) had a higher binding affinity for hormonal receptors and enzymes responsible for hepatic gluconeogenesis compared to standard drugs used in the study. CID 91705405 was also relatively stable over 100 ns of MDS. This compound is therefore revealed to have the potential to modulate both endocrine and metabolic pathways involved in PCOS. The ethanolic extract of P. nigrescens leaves can therefore be considered in the management/treatment of the reproductive and metabolic disorders related to PCOS subject to further experimental validation.

Carcinoma espinocelular da base do chifre, bilateral e simétrico, em vaca com distúrbio hormonal ˗ relato de caso / [Horn-based squamous cell carcinoma, bilateral and symmetrical in cow with hormonal disorder ˗ case report]

Este trabalho tem por objetivo descrever um caso de carcinoma espinocelular da base do chifre, bilateral e simétrico, em uma vaca e discutir a questão hormonal, possivelmente envolvida na patogênese da doença. Tratava-se de uma fêmea bovina, 11 anos, com histórico de emagrecimento progressivo, presença de massas exofíticas na base de ambos os chifres e em anestro por muitos anos. Foi realizada biopsia incisional de ambas as lesões para exame histopatológico e dosagens hormonais. Devido à progressão do quadro clínico, optou-se pela eutanásia, seguida dos exames necroscópico e histopatológico. O exame histopatológico revelou tratar-se de um carcinoma espinocelular infiltrativo bem diferenciado, e as dosagens hormonais apresentaram alterações nos níveis do hormônio luteinizante, folículo estimulante e estrógenos totais. Apesar de existirem descrições de carcinomas espinocelulares da base do chifre, ainda não havia relatos da ocorrência do mesmo bilateral e em uma vaca com distúrbios hormonais.(AU)

The objective of this study was to describe a case of bilateral and symmetrical squamous cell carcinoma from the horn base in a cow and to discuss the hormonal question, possibly involved in its pathogenesis. A 11-year-old beef cow presenting a history of progressive thinning, presence of exophytic masses at the base of both horns and anestrous for many years was assisted. An incisional biopsy of both lesions was performed for histopathological examination and hormonal dosages. Due to the clinical progression, euthanasia followed by necroscopic and histopathological examination was carried out. Histopathological examination revealed a well differentiated infiltrative squamous cell carcinoma and the hormonal dosages presented changes in luteinizing hormone, follicle stimulating and total estrogen levels. Although there are descriptions of basal squamous cell carcinoma of the horn, there were still no reports of the occurrence of the same bilateral in a cow with hormonal disorders.(AU)

The ratio of exogenous Luteinizing hormone to Follicle stimulating hormone administered for controlled ovarian stimulation is associated with oocytes' number and competence.

We performed a retrospective study aiming to study the relationship between the ratio of the exogenous luteinizing hormone to follicle stimulating hormone (LH/FSH) administrated for controlled ovarian stimulation (COS) and the number and competence of the oocytes retrieved for in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI). Eight hundred sixty-eight consecutive infertile patients (mean age 34.54 ± 4.01 years, mean anti-Müllerian hormone (AMH) 2.94 ± 2.07 ng/ml) treated with long agonist protocol and a mixed gonadotropin protocol (human menopausal gonadotropin in association with recombinant FSH (recFSH)) who performed IVF/ICSI between January 2013 and February 2016, were included. Patients with severe male factor were excluded. LH/FSH was calculated based on total doses of the two gonadotropins. We found, after adjustment for confounders, a positive relationship between LH/FSH and the retrieved oocytes' (ß = 0.229, P<0.0001) and zygotes' number (ß = 0.144, P<0.0001) in the entire study group and in subgroups according to age (<35 and ≥35 years) and ovarian reserve (AMH < 1.1 and ≥ 1.1 ng/ml). The fertilization rate was positively associated with LH/FSH in patients with LH/FSH in the lowest three quartiles (below 0.77) (ß = 0.096, P=0.034). However, patients in the fourth quartile of LH/FSH had a lower fertilization rate as compared with patients in quartiles 1-3 which, after adjustment for covariates, was only marginally negatively related with LH/FSH (ß = -0.108, P=0.05). In conclusion, our results suggest that the adequate LH/FSH administrated during COS can improve the oocytes' and zygotes' number in IVF/ICSI cycles, but also the fertilization rate when a certain proportion of LH/FSH is not exceeded.

PGC-1α protects against oxidized low-density lipoprotein and luteinizing hormone-induced granulosa cells injury through ROS-p38 pathway.

Obese women with polycystic ovary syndrome (PCOS) often suffer from ovulation failure, which may be driven by granulosa cells (GCs) injury caused by increased levels of circulating oxidized low-density lipoprotein (ox-LDL) and luteinizing hormone (LH). PGC-1α may play an important role in this pathophysiological processes. However, the effect and the potential mechanism of PGC-1α on GCs injury evoked by obese PCOS is fully unclear. To investigate the protective effect and the potential mechanism of PGC-1α on GCs injury evoked by ox-LDL + LH stimulation. Patients with PCOS and women of normal reproductive age who undergoing egg retrievals and consenting for this research were collected. Those women were divided into normal-weight non-PCOS group, obese non-PCOS group, normal-weight PCOS group and obese PCOS group according to the body mass index (BMI) and PCOS diagnosis. Follicular fluid was collected and primary GCs were isolated. The levels of LH and ox-LDL in follicular fluid in the four groups were measured. And, the expressions of PGC-1α, cell apoptosis and ROS generation in primary GCs in the four groups were evaluated. After GCs from women of normal reproductive age at normal-weight pre-treated with adenovirus encoding PGC-1α (Ad-PGC-1α) prior to ox-LDL + LH treatment in vitro, the cell viability, apoptosis, apoptosis-related proteins expressions and ROS generation were evaluated by CCK-8 assay, AnnexinV/PI double staining, Western blot and H2DCF-DA staining, respectively. The expression of PGC-1α was significantly decreased, whereas the cell apoptosis and ROS generation were significantly increased in GCs of PCOS group, especially obese PCOS group. Our data also revealed that over-expression of PGC-1α in GCs from women of normal reproductive age at normal-weight markedly inhibited cell injury, ROS generation and p38 activation, accompanied by increased Bcl-2 expression, decreased Bax and cleaved caspase-3 expressions induced by ox-LDL + LH stimulation. Ox-LDL + LH-induced cell apoptosis was abrogated by attenuation of ROS generation or p38 activation. Attenuation of ROS generation reversed ox-LDL + LH-induced p38 activation, however, p38 inhibitors had an effect on ROS generation. Our findings suggested that PGC-1α protected against ox-LDL + LH-induced GCs injury through inhibiting cell apoptosis. And, the mechanism may be related to the inhibition of ROS-initiated p38 pathway. Our data indicated that PGC-1α may be a potential therapeutic target for obese PCOS.

Recombinant luteinizing hormone supplementation in assisted reproductive technology: a systematic review.

OBJECTIVE: To assess the role of recombinant human LH (r-hLH) supplementation in ovarian stimulation for ART in specific subgroups of patients. DESIGN: Systematic review. SETTING: Centers for reproductive care. PATIENT(S): Six populations were investigated: 1) women with a hyporesponse to recombinant human FSH (r-hFSH) monotherapy; 2) women at an advanced reproductive age; 3) women cotreated with the use of a GnRH antagonist; 4) women with profoundly suppressed LH levels after the administration of GnRH agonists; 5) normoresponder women to prevent ovarian hyperstimulation syndrome; and 6) women with a "poor response" to ovarian stimulation, including those who met the European Society for Human Reproduction and Embryology Bologna criteria. INTERVENTION(S): Systematic review. MAIN OUTCOME MEASURE(S): Implantation rate, number of oocytes retrieved, live birth rate, ongoing pregnancy rate, fertilization rate, and number of metaphase II oocytes. RESULT(S): Recombinant hLH supplementation appears to be beneficial in two subgroups of patients: 1) women with adequate prestimulation ovarian reserve parameters and an unexpected hyporesponse to r-hFSH monotherapy; and 2) women 36-39 years of age. Indeed, there is no evidence that r-hLH is beneficial in young (<35 y) normoresponders cotreated with the use of a GnRH antagonist. The use of r-hLH supplementation in women with suppressed endogenous LH levels caused by GnRH analogues and in poor responders remains controversial, whereas the use of r-hLH supplementation to prevent the development of ovarian hyperstimulation syndrome warrants further investigation. CONCLUSION(S): Recombinant hLH can be proposed for hyporesponders and women 36-39 years of age.

Addition of neither recombinant nor urinary luteinizing hormone was associated with an improvement in the outcome of autologous in vitro fertilization/intracytoplasmatic sperm injection cycles under regular clinical settings: a multicenter observational analysis.

OBJECTIVE: To determine whether the addition of either urinary or recombinant LH in patients undergoing routine clinical care improved the outcome in terms of the number of oocytes recovered for insemination or the delivery rate per initiated cycle. DESIGN: Cohort analysis. PATIENT(S): Couples undergoing IVF/ICSI in 158 institutions in 15 countries in Latin America. SETTING: In vitro fertilization clinics. INTERVENTION(S): We compared the outcome of three different protocols of COH, including rFSH only, rFSH plus rLH, and rFSH plus hMG. MAIN OUTCOME MEASURE(S): The number of mature oocytes recovered and inseminated; proportion of ETs at the blastocyst stage; clinical pregnancy, miscarriage, and delivery rates; proportion of cycles with embryo cryopreservation; and mean number of embryos cryopreserved. RESULT(S): After correcting for the age of the female partner, body mass index, number of embryos transferred, and stage of embryo development at transfer, we found that LH addition was not associated with an increase in the mean number of metaphase II oocytes inseminated or with an increase in the delivery rate or changes in the miscarriage rate. CONCLUSION(S): Our study strongly suggests that in routine clinical practice, the type of controlled ovarian stimulation-FSH alone or in combination with LH-has little impact on the outcome of assisted reproductive technology; therefore a more friendly and accessible alternative should be favored.

Efficacy and Safety of Pergoveris in Assisted Reproductive Technology--ESPART: rationale and design of a randomised controlled trial in poor ovarian responders undergoing IVF/ICSI treatment.

INTRODUCTION: The results of a recent meta-analysis showed that adding recombinant human luteinising hormone (r-hLH) to recombinant human follicle-stimulating hormone (r-hFSH) for ovarian stimulation was beneficial in poor responders, resulting in a 30% relative increase in the clinical pregnancy rate compared with r-hFSH monotherapy. However, a limitation of the meta-analysis was that the included studies used heterogeneous definitions of poor ovarian response (POR). Furthermore, the use of r-hLH supplementation during ovarian stimulation is a topic of ongoing debate, and well-designed, adequately powered, multicentre, randomised controlled trials in this setting are warranted. Therefore, the objective of the ESPART trial is to explore the possible superiority of a fixed-dose combination of r-hFSH plus r-hLH over r-hFSH monotherapy in patients with POR, as per a definition aligned with the European Society of Human Reproduction and Embryology (ESHRE) Bologna criteria. METHODS AND ANALYSIS: Phase III, randomised, single-blind, parallel-group trial in women undergoing in vitro fertilisation and/or intracytoplasmic sperm injection. Approximately 946 women aged 18-<41 years from 18 countries will be randomised (1:1) to receive a fixed-dose combination of r-hFSH plus r-hLH in a 2:1 ratio (Pergoveris) or r-hFSH monotherapy (GONAL-f). The primary end point is the total number of retrieved oocytes per participant. Secondary end points include: ongoing pregnancy rate, live birth rate, implantation rate, biochemical pregnancy rate and clinical pregnancy rate. Safety end points include: incidence and severity of ovarian hyperstimulation syndrome, and of adverse events and serious adverse events. ETHICS AND DISSEMINATION: The study will be performed in accordance with ethical principles that have their origin in the Declaration of Helsinki, with the International Conference on Harmonisation-Good Clinical Practice guidelines and all applicable regulatory requirements. All participants will provide written informed consent prior to entry. The results of this study will be publically disseminated. TRIAL REGISTRATION NUMBERS: ClinicalTrials.gov identifier: NCT02047227; EudraCT Number: 2013-003817-16; Clinical Trial Protocol Number: EMR200061-005 V.3.0, 15 April 2014.

Human steroidogenesis: implications for controlled ovarian stimulation with exogenous gonadotropins.

In the menstrual cycle, the mid-cycle surge of gonadotropins (both luteinising hormone [LH] and follicle-stimulating hormone [FSH]) signals the initiation of the periovulatory interval, during which the follicle augments progesterone production and begins to luteinise, ultimately leading to the rupture of the follicle wall and the release of an oocyte. The administration of gonadotropins in controlled ovarian stimulation (COS) leads to supraphysiological steroid concentrations of a very different profile compared with those seen during natural cycles. It has been suggested that these high steroid concentrations cause alterations in endometrial development, affecting oocyte viability in assisted reproductive technology. Furthermore, it has been proposed that elevated progesterone levels have a negative effect on the reproductive outcome of COS. This may arise from an asynchrony between embryo stage and endometrium status at the window of implantation. The regulation of progesterone production by the developing follicles during COS is a complicated interplay of hormonal systems involving the theca and granulosa cells, and the effect of the actions of both LH and FSH. The present paper reviews current knowledge of the regulation of progesterone in the human ovary during the follicular phase and highlights areas where knowledge remains limited. In this review, we provide in-depth information outlining the regulation and function of gonadotropins in the complicated area of steroidogenesis. Based on current evidence, it is not clear whether the high levels of progesterone produced during COS have detrimental effects on fertility.

A review of luteinising hormone and human chorionic gonadotropin when used in assisted reproductive technology.

Gonadotropins extracted from the urine of post-menopausal women have traditionally been used to stimulate folliculogenesis in the treatment of infertility and in assisted reproductive technology (ART). Products, such as human menopausal gonadotropin (hMG), consist not only of a mixture of the hormones, follicle-stimulating hormone (FSH), luteinising hormone (LH) and human chorionic gonadotropin (hCG), but also other biologically active contaminants, such as growth factors, binding proteins and prion proteins. The actual amount of molecular LH in hMG preparations varies considerably due to the purification process, thus hCG, mimicking LH action, is added to standardise the product. However, unlike LH, hCG plays a different role during the natural human menstrual cycle. It is secreted by the embryo and placenta, and its main role is to support implantation and pregnancy. More recently, recombinant gonadotropins (r-hFSH and r-hLH) have become available for ART therapies. Recombinant LH contains only LH molecules. In the field of reproduction there has been controversy in recent years over whether r-hLH or hCG should be used for ART. This review examines the existing evidence for molecular and functional differences between LH and hCG and assesses the clinical implications of hCG-supplemented urinary therapy compared with recombinant therapies used for ART.

Split daily recombinant human LH dose in hypogonadotrophic hypogonadism: a nonrandomized controlled pilot study.

This prospective controlled nonrandomized pilot study was conducted to investigate whether split daily doses of recombinant human LH (rHLH) is more efficacious than the single daily dose in supporting follicular development and ovulation in primary hypogonadotrophic hypogonadism (HH). Twenty-seven women with HH received a 150 IU fixed daily subcutaneous dose of recombinant human FSH, supplemented by 75 IU daily dose of rHLH given either as a single dose (n=9; single-dose group) or four equally divided doses (n=18; split-dose group). Ovulation was defined by three efficacy end points: at least one follicle ⩾17mm in diameter, pre-ovulatory serum oestradiol ⩾400pmol/l and a midluteal progesterone ⩾25nmol/l. Although lacking statistical significance, the proportion of women in the rHLH split-dose group who fulfilled all three end points was higher than the single-dose group (72.2% versus 55.6%). Women in the split-dose group achieved higher serum oestradiol concentrations per follicle, endometrial thickness measurements and numbers of follicles than in the single-dose group (not statistically significant). The odds ratio for ovulation rate was 2.08 (not statistically significant). There were no serious untoward side effects. Administering rHLH in split daily doses could provide superior results compared with the traditional single daily dose. We conducted this clinical study to investigate whether a split daily dose protocol of recombinant human LH (rHLH) is more efficacious than the single daily dose in supporting follicular development and ovulation in primary hypogonadotrophic hypogonadism (HH). HH is an uncommon entity that can lead to very low or undetectable serum gonadotrophin concentrations. It manifests in anovulation, amenorrhoea and subsequent infertility. Twenty-seven women with HH received a 150 IU fixed daily subcutaneous dose of recombinant human FSH, supplemented by a 75 IU daily dose of rHLH given either as a single dose (n=9; single-dose group) or four equally divided doses (n=18; split-dose group). Ovulation was defined by these three efficacy end points: at least one follicle ⩾17mm in mean diameter, pre-ovulatory serum oestradiol concentration ⩾400pmol/l and a midluteal progesterone concentration ⩾25nmol/l. The proportion of women in the rHLH split-dose group who fulfilled all three end points was higher than the single-dose group (72.2% versus 55.6%). Women in the split-dose group achieved higher serum oestradiol concentrations per follicle, endometrial thickness measurements and numbers of follicles than in the single-dose group, without statistical significance. Women who received the split-dose regimen were more likely to have ovulation than the other group. We had no serious problematic side effects. Our results suggest that administering rHLH in split daily doses could provide superior results compared to the traditional single daily dose.

LH supplementation in mild stimulations cycles without pituitary suppression: a retrospective analysis.

A cohort of patients addressed to a mild stimulation protocol was retrospectively analysed aiming at evaluating the effect of a luteinizing hormone (LH) activity containing stimulation compared to a pure follicle-stimulating hormone (FSH) drive in absence of any pituitary suppression. Due to a referral bias, the two groups (human FSH (hFSH) n = 210; hMG n = 105) were imbalanced for age with the hFSH group (mean age 38.4) being significantly older than the hMG group (mean age 36.8). But the clinical pregnancy rates (20%) did not differ between the groups. Secondary outcome variables showed a higher number of oocytes retrieved (3.02 vs. 2.31) and higher estradiol levels (1148 vs. 820) in the hMG/younger group whereas the fertilization rate (FR) was higher (54.8 vs. 63.8) in the FSH older/group. In spite of the LH content in the hMG product (~10 IU per vial), the LH concentration on the day of human chorionic gonadotropin (hCG) was higher, although non-significantly, in the hFSH group. We suppose hCG contained in hMG inhibited to some extent the natural release of LH from the non-suppressed pituitary. Concluding, the mild stimulation clinical pregnancy rates are satisfactory independently of the treatment choice. The hMG group showed a trend for a lower efficacy. This phenomenon might be limited to non suppressed cycles, but should be taken in due account also when designing full dose controlled ovarian hyperstimulation (COH) treatments.

[Ovarian hyperstimulation syndrome: pathophysiology, risk factors, prevention, diagnosis and treatment]. / Le syndrome d'hyperstimulation ovarienne : physiopathologie, facteurs de risque, prévention et prise en charge.

The ovarian hyperstimulation syndrome is a major complication of ovulation induction for in vitro fertilization, with severe morbidity and possible mortality. Whereas its pathophysiology remains ill-established, the VEGF may play a key role as well as coagulation disturbances. Risk factors for severe OHSS may be related to patients characteristics or to the management of the ovarian stimulation. Two types of OHSS are usually distinguished: the early OHSS, immediately following the ovulation triggering and a later and more severe one, occurring in case of pregnancy. As no etiologic treatment is available, the therapeutic management of OHSS should focus on its related-complications. Thrombotic complications that can occur in venous or arterial vessels represent the major risk of OHSS, possibly conducting to myocardial infarction and cerebrovascular accidents. Once the OHSS is diagnosed, prevention of thrombotic accidents remains the major issue.

A novel method of luteal supplementation with recombinant luteinizing hormone when a gonadotropin-releasing hormone agonist is used instead of human chorionic gonadotropin for ovulation triggering: a randomized prospective proof of concept study.

This pilot study investigates the role of luteal supplementation with recombinant LH in an attempt to reverse the poor reproductive outcome previously noticed after GnRH-agonist triggering of final oocyte maturation for IVF. Similar implantation rates were achieved with the novel recombinant LH luteal supplementation scheme compared with the standard luteal P protocol (25.0% vs. 26.7%, respectively). No cases of ovarian hyperstimulation syndrome (OHSS) were noticed in either group.

A 2:1 formulation of follitropin alfa and lutropin alfa in routine clinical practice: a large, multicentre, observational study.

BACKGROUND: A 2:1 (150 IU:75 IU) follitropin alfa:lutropin alfa formulation has been developed. A 3-year post-marketing surveillance study is ongoing in Germany to explore the use of this formulation in routine clinical practice. MATERIALS AND METHODS: An 11-month interim analysis of data from assisted reproductive technology (ART) cycles only is described. RESULTS: Data were available from 857 patients undergoing 919 cycles of ART at 19 centres. Most patients (58.7%) were aged ≥ 35 years, and many (41.3%) were undergoing their first ART cycle. Main reasons cited by physicians for prescribing this formulation were poor response in a previous treatment cycle (n = 303) and low basal luteinizing hormone (LH) level (n = 107). Mean (standard deviation) duration of ovarian stimulation was 10.8 (2.6) days. In 90.7% of cycles, the 2:1 formulation was administered throughout the stimulation period. Most frequent LH daily dose was 75 IU. Embryo transfer was conducted in 741 cycles; clinical pregnancy rate per transfer was 27.5%. Three cases of ovarian hyperstimulation syndrome developed in three patients (3/741 [0.4%] cycles); one required hospitalization. No other major safety events were reported. CONCLUSION: This interim analysis shows that use of the 2:1 formulation for ovarian stimulation during routine ART procedures is effective in achieving clinical pregnancies and is associated with a positive safety profile.

Recombinant human follicular stimulating hormone and recombinant human luteinizing hormone in a 2:1 ratio combination. Pharmacological characteristics and clinical applications.

IMPORTANCE OF THE FIELD: A new fixed combination of recombinant human follicle stimulating hormone (r-hFSH) and recombinant human luteinizing hormone (r-hLH) at a 2:1 ratio has been recently developed to induce ovulation in patients with hypogonadotrophic hypogonadism. Whether or not this compound is useful for controlled ovarian stimulation for in vitro fertilization is still a matter of debate. AREAS COVERED IN THIS REVIEW: Description of pharmacological and clinical aspects of this new product, through the analysis of the Phase I, II and II trials and post-marketing clinical randomized trials, performed since the initial assays in 1998 to nowadays. WHAT THE READER WILL GAIN: After reading this review the reader will understand the pharmacological aspects of this new compound, in terms of efficacy and safety, and will have an update of the potential role of r-LH administration in controlled ovarian stimulation for in vitro fertilization. TAKE HOME MESSAGE: The 2:1 combination of r-hFSH and r-hLH has been seen as an optimum preparation in terms of safety and clinical efficacy in hypogonatrophic hypogonadism patients. Its use in ovarian stimulation for IVF remains controversial, as the target population that may receive a benefit of it is not well defined.

Follicular development induced by recombinant luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in anovulatory women with LH and FSH deficiency: evidence of a threshold effect.

OBJECTIVE: To assess the requirement for luteinizing hormone (LH) in women deficient in LH and follicle-stimulating hormone (FSH). RESEARCH DESIGN AND METHODS: A prospective, randomized, parallel-group, multicentre study was carried out in tertiary care and academic medical centres. Women with anovulatory amenorrhoea > or = 1 year, serum oestradiol (E(2)) < 60 pg/mL (< 220 pmol/L) and low normal serum gonadotrophins were randomized in cycle A to a fixed daily dose of recombinant human (r-h) FSH (150 IU) and r-hLH 0, 25, 75 or 225 IU. Cycles B and C were not randomized. MAIN OUTCOME MEASURES: Follicular development, ovulation and luteinization. RESULTS: In cycle A, follicular development was achieved by 63.6% (7/11), 100% (9/9), 72.7% (8/11) and 66.7% (6/9) of patients who received r-hFSH and r-hLH 0, 25, 75 or 225 IU/day, respectively (p = not significant). Among patients with basal serum LH of < 1.2 IU/L, a dose-response relationship of r-hLH to follicular development was observed (p = 0.039). Fourteen of 34 patients (41.2%) wishing to conceive became pregnant. Among patients with hypogonadotrophic hypogonadism (HH) treated with r-hFSH alone, a transition from LH dependence to independence was observed between basal LH values of > or = 1.2 IU/L and < or = 1.6 IU/L. The r-hLH was well tolerated and no serious adverse events occurred during treatment. The most common treatment-related events were related to the reproductive system and the gastrointestinal tract. CONCLUSIONS: Recombinant human LH provides a safe treatment option for women with HH. This small study also provided evidence suggestive of an LH threshold: follicular development was suboptimal when less than 75 IU/day r-hLH was administered.

Recombinant LH (lutropin alfa) for the treatment of hypogonadotrophic women with profound LH deficiency: a randomized, double-blind, placebo-controlled, proof-of-efficacy study.

OBJECTIVE: To confirm the safety and efficacy of 75 IU lutropin alfa with concomitant follitropin alfa in inducing follicular development in women with profound gonadotrophin deficiency. DESIGN: Double-blind, randomized, placebo-controlled trial conducted in 25 medical centres in four countries. PATIENTS: Thirty-nine patients with LH < 1.2 IU/l and FSH < 5.0 IU/l were treated with concomitant 75 IU lutropin alfa and 150 IU follitropin alfa or concomitant placebo and 150 IU follitropin alfa. MEASUREMENTS: Primary efficacy end-point (intent-to-treat): follicular development defined by (i) at least one follicle >or= 17 mm; (ii) serum E(2) level >or= 400 pmol/l on day of hCG administration (DhCG); and (iii) mid-luteal phase progesterone level >or= 25 nmol/l. RESULTS: In the analysis of evaluable patients, 66.7% (16 of 24) of patients given lutropin alfa achieved follicular development compared with 20.0% (2 of 10) of patients receiving placebo (P = 0.023). In the intent-to-treat analysis, follicular development was achieved in 65.4% (17 of 26) of patients receiving lutropin alfa and 15.4% (2 of 13) of patients receiving placebo (P = 0.006). The statistical difference between treatment groups was preserved when over-response leading to cycle cancellation was analysed as a failed response (P = 0.034). Lutropin alfa was well tolerated. CONCLUSION: Subcutaneous co-administration of 75 IU lutropin alfa with follitropin alfa is safe and effective in inducing follicular development in women with profound gonadotrophin deficiency.