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1.
Eur J Obstet Gynecol Reprod Biol ; 222: 119-125, 2018 Mar.
Article in English | MEDLINE | ID: mdl-29408742

ABSTRACT

STUDY OBJECTIVES: To investigate the effect of N312S polymorphism in the LHCGR gene as a predictive pharmacogenetic marker on clinical and embryological parameters and determining the need of r-hLH supplementation combine with r-hFSH in patients undergoing ART treatment. STUDY DESIGN: In a cross-sectional study, a retrospective analysis of women (n = 553), who underwent controlled ovarian stimulation treatment protocol was conducted during the years 2012-2014. R-hFSH (Gonal-F, Merck Serono) was administered to all patients undergoing ART cycle after initiating long luteal gonadotrophin-releasing hormone (GnRH) agonist down-regulation. R-hLH was supplemented based on P.C. Wong criteria. N312S genotype was determined using sequencing methodology. The mean r-hFSH, r-hLH doses, total number of oocytes, cleavage rates of embryos and clinical pregnancy were recorded. The association between the r-hLH supplementation and LHCGR N312S polymorphism and clinical pregnancy rates was determined using regression analysis by SPSS. RESULTS: 19.7% of women were homozygous for A allele encoding asparagine (N/N), 45.7% were heterozygous (N/S) and 34.6% were homozygous (S/S) for G allele encoding serine. Women heterozygous (N/S) or homozygous (S/S) for serine showed a higher requirement for r-hLH (OR, 95% p-trend = <0.0001) compared to those homozygous for asparagine (N/N). Homozygous G allele was also associated with higher daily and total r-hLH dose per treatment cycle p-trend = <0.0001. Though, the total no of oocytes (14.87 ±â€¯4.95 vs 12.98 ±â€¯5.39 and 13.58 ±â€¯5.45), Gr-I quality embryos (2.61 ±â€¯1.81 vs 2.18 ±â€¯1.96 and 1.98 ±â€¯2.05) were significantly higher in women homozygous for A allele compared to women with heterozygous and homozygous for G allele, clinical pregnancy rates were significantly more in women with for G allele after excluding patients with PCOS and endometriosis conditions (P < 0.04). CONCLUSION: The present findings reveal that women heterozygous and homozygous for G allele required higher doses of r-hLH supplementation and these women were shown to have higher clinical pregnancy rates.


Subject(s)
Drug Resistance/genetics , Growth Hormone-Releasing Hormone/agonists , Infertility, Female/therapy , Luteinizing Hormone/pharmacology , Ovulation Induction , Polymorphism, Single Nucleotide , Receptors, LHRH/genetics , Adult , Amino Acid Substitution , Cohort Studies , Cross-Sectional Studies , Dose-Response Relationship, Drug , Female , Fertility Agents, Female/administration & dosage , Fertility Agents, Female/metabolism , Fertility Agents, Female/pharmacology , Fertilization in Vitro , Follicle Stimulating Hormone/genetics , Follicle Stimulating Hormone/metabolism , Follicle Stimulating Hormone/pharmacology , Genetic Association Studies , Growth Hormone-Releasing Hormone/metabolism , Humans , India , Infertility, Female/genetics , Infertility, Female/metabolism , Luteinizing Hormone/administration & dosage , Luteinizing Hormone/genetics , Luteinizing Hormone/metabolism , Pharmacogenetics/methods , Receptors, LHRH/metabolism , Recombinant Proteins/administration & dosage , Recombinant Proteins/metabolism , Recombinant Proteins/pharmacology , Retrospective Studies
2.
Gynecol Endocrinol ; 33(8): 583-587, 2017 Aug.
Article in English | MEDLINE | ID: mdl-28393578

ABSTRACT

The aim of this review is to analyse the effectiveness of exogenous kisspeptin administration as a novel alternative of triggering oocyte maturation, instead of currently used triggers such as human chorionic gonadotropin (hCG) or gonadotropin releasing hormone (GnRH) agonist, in women undergoing in vitro fertilisation (IVF) treatment. Kisspeptin has been considered a master regulator of two modes of GnRH and hence gonadotropin secretion, pulses and surges. Administration of kisspeptin-10 and kisspeptin-54 induces the luteinising hormone (LH) surge required for egg maturation and ovulation in animal investigations and LH release during the preovulatory phase of the menstrual cycle and hypothalamic amenorrhoea in humans. Exogenous kisspeptin-54 has been successfully administered as a promising method of triggering oocyte maturation, following ovarian stimulation with gonadotropins and GnRH antagonists in women undergoing IVF, due to its efficacy considering achieved pregnancy rates compared to hCG and GnRH agonists. Also, its safety in patients at high risk of developing ovarian hyperstimulation syndrome is noteworthy. Nevertheless, further studies would be desirable to establish the optimal trigger of egg maturation and to improve the reproductive outcome for women undergoing IVF treatment.


Subject(s)
Fertility Agents, Female/therapeutic use , Fertilization in Vitro , Infertility, Female/therapy , Kisspeptins/therapeutic use , Oogenesis/drug effects , Ovulation Induction , Adult , Animals , Female , Fertility Agents, Female/adverse effects , Fertility Agents, Female/metabolism , Fertilization in Vitro/adverse effects , Humans , Kisspeptins/adverse effects , Kisspeptins/genetics , Kisspeptins/metabolism , Ovarian Hyperstimulation Syndrome/chemically induced , Ovarian Hyperstimulation Syndrome/epidemiology , Ovarian Hyperstimulation Syndrome/prevention & control , Ovulation/drug effects , Ovulation Induction/adverse effects , Peptide Fragments/adverse effects , Peptide Fragments/genetics , Peptide Fragments/metabolism , Peptide Fragments/therapeutic use , Pregnancy , Pregnancy Rate , Recombinant Proteins/adverse effects , Recombinant Proteins/metabolism , Recombinant Proteins/therapeutic use , Risk
3.
Drug Dev Ind Pharm ; 43(3): 399-408, 2017 Mar.
Article in English | MEDLINE | ID: mdl-27783532

ABSTRACT

OBJECTIVE: The objective of this study is to develop and characterize in situ thermosensitive gels for the vaginal administration of sildenafil as a potential treatment of endometrial thinning occurring as a result of using clomiphene citrate for ovulation induction in women with type II eugonadotrophic anovulation. While sildenafil has shown promising results in the treatment of infertility in women, the lack of vaginal pharmaceutical preparation and the side effects associated with oral sildenafil limit its clinical effectiveness. METHODS: Sildenafil citrate in situ forming gels were prepared using different grades of Pluronic® (PF-68 and PF-127). Mucoadhesive polymers as sodium alginate and hydroxyethyl cellulose were added to the gels in different concentrations and the effect on gel properties was studied. The formulations were evaluated in terms of viscosity, gelation temperature (Tsol-gel), mucoadhesion properties, and in vitro drug release characteristics. Selected formulations were evaluated in women with clomiphene citrate failure due to thin endometrium (Clinicaltrial.gov identifier NCT02766725). RESULTS: The Tsol-gel decreased with increasing PF-127 concentration and it was modulated by addition of PF-68 to be within the acceptable range of 28-37 °C. Increasing Pluronic® concentration increased gel viscosity and mucoadhesive force but decreased drug release rate. Clinical results showed that the in situ sildenafil vaginal gel significantly increased endometrial thickness and uterine blood flow with no reported side effects. Further, these results were achieved at lower frequency and duration of drug administration. CONCLUSION: Sildenafil thermosensitive vaginal gels might result in improved potential of pregnancy in anovulatory patients with clomiphene citrate failure due to thin endometrium.


Subject(s)
Adhesives/administration & dosage , Clomiphene/administration & dosage , Drug Delivery Systems/methods , Fertility Agents, Female/administration & dosage , Ovulation/drug effects , Sildenafil Citrate/administration & dosage , Adhesives/metabolism , Administration, Intravaginal , Adult , Animals , Clomiphene/metabolism , Double-Blind Method , Female , Fertility Agents, Female/metabolism , Follow-Up Studies , Gels , Hot Temperature , Humans , Infertility, Female/diagnostic imaging , Infertility, Female/drug therapy , Infertility, Female/metabolism , Ovulation/metabolism , Pilot Projects , Prospective Studies , Sildenafil Citrate/metabolism , Swine , Young Adult
4.
Hum Reprod ; 30(2): 284-98, 2015 Feb.
Article in English | MEDLINE | ID: mdl-25432925

ABSTRACT

STUDY QUESTION: Does insulin-like growth factor 1 (IGF1) increase adhesion competency of blastocysts to increase attachment to uterine epithelial cells in vitro? SUMMARY ANSWER: IGF1 increases apical fibronectin on blastocysts to increase attachment and invasion in an in vitro model of implantation. WHAT IS KNOWN ALREADY: Fibronectin integrin interactions are important in attachment of blastocysts to uterine epithelial cells at implantation. STUDY DESIGN, SIZE, DURATION: Mouse blastocysts (hatched or near completion of hatching) were cultured in serum starved (SS) medium with varying treatments for 24, 48 or 72 h. Treatments included 10 ng/ml IGF1 in the presence or absence of the PI3 kinase inhibitor LY294002, an IGF1 receptor (IGF1R) neutralizing antibody or fibronectin. Effects of treatments on blastocysts were measured by attachment of blastocysts to Ishikawa cells, blastocyst outgrowth and fibronectin and focal adhesion kinase (FAK) localization and expression. Blastocysts were randomly allocated into control and treatment groups and experiments were repeated a minimum of three times with varying numbers of blastocysts used in each experiment. FAK and integrin protein expression on Ishikawa cells was quantified in the presence or absence of IGF1. PARTICIPANTS/MATERIALS, SETTING, METHODS: Fibronectin expression and localization in blastocysts was studied using immunofluorescence and confocal microscopy. Global surface expression of integrin αvß3, ß3 and ß1 was measured in Ishikawa cells using flow cytometry. Expression levels of phosphorylated FAK and total FAK were measured in Ishikawa cells and blastocysts by western blot and image J analysis. Blastocyst outgrowth was quantified using image J analysis. MAIN RESULTS AND THE ROLE OF CHANCE: The presence of IGF1 significantly increased mouse blastocyst attachment to Ishikawa cells compared with SS conditions (P < 0.01). IGF1 treatment resulted in distinct apical fibronectin staining on blastocysts, which was reduced by the PI3 kinase inhibitor LY294002. This coincided with a significant increase in blastocyst outgrowth in the presence of IGF1 (P < 0.01) or fibronectin (P < 0.001), which was abolished by LY294002 (P < 0.001). Apical expression of integrin αvß3, ß3 and ß1 in Ishikawa cells was unaltered by IGF1. However, IGF1 increased phosphorylated FAK (P < 0.05) and total FAK expression in Ishikawa cells. FAK signalling is linked to integrin activation and can affect the integrins' ability to bind and recognize extracellular matrix proteins such as fibronectin. Treatment of blastocysts with IGF1 before co-culture with Ishikawa cells increased their attachment (P < 0.05). This effect was abolished in the presence of LY294002 (P < 0.001) or an IGF1R neutralizing antibody (P < 0.05). LIMITATIONS, REASONS FOR CAUTION: This study uses an in vitro model of attachment that uses mouse blastocysts and human endometrial cells. This involves a species crossover and although this use has been well documented as a model for attachment (as human embryo numbers are limited) the results should be interpreted carefully. WIDER IMPLICATIONS OF THE FINDINGS: This study presents mechanisms by which IGF1 improves attachment of blastocysts to Ishikawa cells and documents for the first time how IGF1 can increase adhesion competency in blastocysts. Failure of the blastocyst to implant is the major cause of human assisted reproductive technology (ART) failure. As growth factors are absent during embryo culture, their addition to embryo culture medium is a potential avenue to improve IVF success. In particular, IGF1 could prove to be a potential treatment for blastocysts before transfer to the uterus in an ART setting.


Subject(s)
Blastocyst/drug effects , Cell Membrane/drug effects , Endometrium/drug effects , Fertility Agents, Female/pharmacology , Fibronectins/agonists , Insulin-Like Growth Factor I/pharmacology , Up-Regulation/drug effects , Animals , Blastocyst/cytology , Blastocyst/metabolism , Cell Adhesion/drug effects , Cell Line , Cell Membrane/metabolism , Coculture Techniques , Ectogenesis/drug effects , Embryo Culture Techniques , Endometrium/metabolism , Enzyme Inhibitors/pharmacology , Female , Fertility Agents, Female/metabolism , Fibronectins/metabolism , Focal Adhesion Protein-Tyrosine Kinases/metabolism , Humans , Insulin-Like Growth Factor I/genetics , Insulin-Like Growth Factor I/metabolism , Mice, Inbred Strains , Phosphatidylinositol 3-Kinase/metabolism , Phosphoinositide-3 Kinase Inhibitors , Protein Transport/drug effects , Receptor, IGF Type 1/antagonists & inhibitors , Receptor, IGF Type 1/metabolism , Recombinant Proteins/metabolism , Recombinant Proteins/pharmacology
5.
J Endocrinol Invest ; 34(9): 685-91, 2011 Oct.
Article in English | MEDLINE | ID: mdl-21586896

ABSTRACT

AIM: The aims of the study were to understand the association between insulin-like factor 3 (INSL3) and functional ovarian hyperandrogenism (FOH) in PCOS and the regulatory role played by LH. SUBJECTS AND METHODS: Fifteen PCOS women were classified as FOH (FOH-PCOS, no.=8) and non-FOH (NFOH-PCOS, no.=7) according to the response of 17OH-progesterone to buserelin (a GnRH analogue) with respect to 15 controls. FOH-PCOS and NFOH-PCOS were compared for basal INSL3 levels. In addition, the effect of buserelin on INSL3 concentrations and the relationship between basal and buserelin-stimulated LH and 17OH-progesterone and INSL3 were evaluated. RESULTS: Basal INSL3 levels were higher in FOH-PCOS than NFOH-PCOS (p=0.001) and controls (p=0.001), whereas they did not differ between NFOHPCOS and controls. In addition, FOH-PCOS had a higher response of LH to buserelin with respect to NFOH-PCOS. Within all PCOS women the levels of INSL3 positively correlated with free testosterone (p=0.022) and negatively with SHBG (r= p=0.031). Moreover, positive correlations with the absolute increase of 17OH-progesterone (p<0.001) and with the LH area under the curve (p=0.001) after buserelin administration were found. In the multiple regression analysis INSL3 persisted significantly correlated only with 17OH-progesterone response to buserelin. Finally, INSL3 was not significantly modified after buserelin administration either in FOHPCOS or in NFOH-PCOS. CONCLUSIONS: These data suggest that INSL3 is related to FOH in PCOS women, but this association seems not to be mediated by LH, further reinforcing the concept that a pathophysiological heterogeneity for ovarian hyperandrogenism in PCOS exists.


Subject(s)
Hyperandrogenism/blood , Hyperandrogenism/physiopathology , Insulin/blood , Ovary/physiopathology , Polycystic Ovary Syndrome/physiopathology , 17-alpha-Hydroxyprogesterone/metabolism , Adolescent , Adult , Body Mass Index , Buserelin/metabolism , Female , Fertility Agents, Female/metabolism , Gonadotropin-Releasing Hormone/analogs & derivatives , Gonadotropin-Releasing Hormone/metabolism , Humans , Luteinizing Hormone/metabolism , Middle Aged , Ovary/anatomy & histology , Polycystic Ovary Syndrome/blood , Proteins , Young Adult
6.
Fertil Steril ; 95(8): 2784-5, 2011 Jun 30.
Article in English | MEDLINE | ID: mdl-21497348

ABSTRACT

Because of its size of 32 kDa and physicochemical properties, urinary FSH cannot permeate intact skin. We report the first pregnancy after laser microporation and transdermal delivery of FSH for ovarian superovulation as a substitute for SC or IM injections.


Subject(s)
Fertility Agents, Female/administration & dosage , Follicle Stimulating Hormone/administration & dosage , Oocyte Donation , Ovulation Induction/methods , Superovulation/drug effects , Administration, Cutaneous , Embryo Transfer , Female , Fertility Agents, Female/metabolism , Fertilization in Vitro , Follicle Stimulating Hormone/metabolism , Gestational Age , Humans , Pregnancy , Skin/metabolism , Skin Absorption , Transdermal Patch , Treatment Outcome , Twins
7.
Fertil Steril ; 80 Suppl 2: 839-43, 2003 Sep.
Article in English | MEDLINE | ID: mdl-14505762

ABSTRACT

OBJECTIVE: To determine the effects of controlled ovarian hyperstimulation and resultant high levels of E(2) on endometrial HOXA10 expression (a marker of endometrial receptivity). DESIGN: Prospective study. SETTING: University academic medical center. PATIENT(S): Twenty-five women undergoing controlled ovarian hyperstimulation with recombinant FSH and 30 fertile controls. INTERVENTION(S): Endometrium was obtained by Pipelle endometrial biopsy on cycle days 21-25. In addition, Ishikawa cells (a well-differentiated endometrial adenocarcinoma cell line) were treated with either E(2), recombinant FSH, GnRH agonist, or GnRH antagonist. RNA was extracted and analyzed by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). MAIN OUTCOME MEASURE(S): HOXA10 expression. RESULT(S): Endometrial HOXA10 expression in women undergoing controlled ovarian hyperstimulation (COH) with recombinant FSH was not different from that in fertile controls. Estradiol increased HOXA10 expression in Ishikawa cells in a dose-dependent manner from 10(-9) to 10(-7) M. Neither recombinant FSH, GnRH agonist, nor GnRH antagonist altered HOXA10 expression in these cells. CONCLUSION(S): Controlled ovarian hyperstimulation did not inhibit endometrial HOXA10 expression in vivo. In addition, in vitro endometrial cell HOXA10 expression was not altered by either recombinant FSH, GnRH agonist, or GnRH antagonist. COH is unlikely to adversely impact endometrial receptivity.


Subject(s)
Endometrium/metabolism , Follicle Stimulating Hormone/pharmacology , Gonadotropin-Releasing Hormone/analogs & derivatives , Homeodomain Proteins/biosynthesis , Ovulation Induction , Adult , Embryo Implantation/drug effects , Embryo Implantation/physiology , Endometrium/drug effects , Estradiol/metabolism , Female , Fertility Agents, Female/metabolism , Gonadotropin-Releasing Hormone/metabolism , Homeobox A10 Proteins , Homeodomain Proteins/genetics , Hormone Antagonists/metabolism , Humans , Leuprolide/metabolism , Prospective Studies , RNA/chemistry , RNA/genetics , Recombinant Proteins/pharmacology , Reverse Transcriptase Polymerase Chain Reaction , Tumor Cells, Cultured
8.
J Clin Endocrinol Metab ; 88(7): 3360-7, 2003 Jul.
Article in English | MEDLINE | ID: mdl-12843188

ABSTRACT

Loss of function by 11 of 13 naturally occurring mutations in the human GnRH receptor (hGnRHR) was thought to result from impaired ligand binding or effector coupling, but actually results from receptor misrouting. Homo- or heterodimerization of mutant receptors with wild-type (WT) receptors occurs for other G protein-coupled receptors and may result in dominant-negative or -positive effects on the WT receptor. We tested the hypothesis that WT hGnRHR function was affected by misfolded hGnRHR mutants. hGnRHR mutants were found to inhibit the function of WT GnRHR (measured by activation of effector and ligand binding). Inhibition varied depending on the particular hGnRHR mutant coexpressed and the ratio of hGnRHR mutant to WT hGnRHR cDNA cotransfected. The hGnRHR mutants did not interfere with the function of genetically modified hGnRHRs bearing either a deletion of primate-specific Lys(191) or the carboxyl-terminal tail of the catfish GnRHR; these show intrinsically enhanced expression. Moreover, a peptidomimetic antagonist of GnRH enhanced the expression of WT hGnRHR, but not of genetically modified hGnRHR species. The dominant-negative effect of the naturally occurring receptor mutants occurred only for the WT hGnRHR, which has intrinsic low maturation efficiency. The data suggest that this dominant negative effect accompanies the diminished plasma membrane expression as a recent evolutionary event.


Subject(s)
Cell Membrane/metabolism , Evolution, Molecular , Receptors, LHRH/genetics , Receptors, LHRH/metabolism , Amino Acid Sequence , Animals , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Buserelin/metabolism , Buserelin/pharmacology , COS Cells , Fertility Agents, Female/metabolism , Fertility Agents, Female/pharmacology , Gene Expression , Humans , Indoles/pharmacology , Inositol Phosphates/biosynthesis , Iodine Radioisotopes , Molecular Sequence Data , Mutagenesis , Protein Binding/drug effects , Protein Structure, Tertiary , Pyridines/pharmacology , Receptors, LHRH/chemistry , Recombinant Fusion Proteins/chemistry , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/metabolism
9.
Endocr Relat Cancer ; 10(2): 161-7, 2003 Jun.
Article in English | MEDLINE | ID: mdl-12790778

ABSTRACT

Luteinizing hormone-releasing hormone (LHRH) is the key hormone in the control of reproductive functions. In recent years, it has become evident that LHRH might act as a growth modulatory factor in tumors of the reproductive system. We have shown that in prostate cancer cells LHRH is expressed, together with its receptors, to negatively regulate cell proliferation. In these cells, LHRH acts as an antimitogenic factor through the activation of the Gi-cAMP intracellular signaling pathway. More recently, we investigated whether an LHRH-based autocrine system might also be expressed in tumors that are not classically related to the reproductive tract, such as melanoma. Malignant melanoma is known to be characterized not only by a high proliferation rate, but also by an aggressive metastatic behavior. We have demonstrated that both LHRH and LHRH receptors are expressed in human melanoma cells (BLM and Me15392). Activation of LHRH receptors by means of a potent LHRH agonist (Zoladex) significantly inhibited cell proliferation. The LHRH agonist also reduced the ability of melanoma cells to invade a reconstituted basement membrane (Matrigel) and to migrate in response to a chemotactic stimulus. These data indicate that: (a) in prostate cancer cells the LHRH receptor is coupled to a Gi-cAMP signal transduction pathway; (b) LHRH and LHRH receptors are also expressed in tumors that are not classically related to the reproductive system, such as melanoma; in melanoma cells, LHRH might act as an inhibitory factor on both cell proliferation and metastatic behavior. It is suggested that, in melanoma, LHRH receptors might represent a diagnostic marker and a possible molecular target for new therapeutic approaches for this pathology.


Subject(s)
Fertility Agents, Female/pharmacology , Gonadotropin-Releasing Hormone/pharmacology , Neoplasms/pathology , Cell Division/drug effects , Fertility Agents, Female/metabolism , Gonadotropin-Releasing Hormone/metabolism , Humans , Male , Receptors, LHRH/metabolism
10.
Biol Reprod ; 68(4): 1150-6, 2003 Apr.
Article in English | MEDLINE | ID: mdl-12606432

ABSTRACT

The content, binding affinity, and bioactivity of chicken II GnRH (GnRH II) and a stable analogue of GnRH II (GnRH II analogue) in the baboon ovary were studied. Although mammalian GnRH is rapidly degraded by baboon ovarian extracts, we designed a GnRH II analogue that is stable to ovarian enzymatic degradation. This analogue binds to the ovarian membranes with high affinity (41 +/- 3 nM), having 20-fold the affinity of a potent mammalian GnRH analogue. The bioactivity of GnRH II and this GnRH II analogue on the regulation of ovarian progesterone release was compared with that for a potent mammalian GnRH analogue using a baboon granulosa cell culture system. Both GnRH II and GnRH II analogue produced significant inhibition of progesterone release from the granulosa cells (P < 0.03 and P < 0.005, respectively), with a greater reduction observed using the GnRH II analogue. After 24 h in culture, this GnRH II analogue produced a 59% +/- 5% inhibition of progesterone with a concentration as low as 1 nM. Maximal inhibition of 75% +/- 1% was attained with 10 nM GnRH II analogue. The endogenous GnRH II content in the baboon ovary was 5-14 pmoles/g protein. The release of endogenous GnRH II from granulosa cells was observed throughout the 48 h in culture. These studies demonstrated the presence of high enzymatic activity for the degradation of mammalian GnRH in the ovary, whereas this GnRH II analogue was stable. High-affinity binding sites for this GnRH II analogue were also found. GnRH II and this GnRH II analogue can regulate progesterone production from baboon granulosa cells, suggesting that GnRH II is a potent regulator of ovarian function.


Subject(s)
Gonadotropin-Releasing Hormone/physiology , Ovary/physiology , Animals , Binding Sites , Binding, Competitive , Buserelin/metabolism , Buserelin/pharmacology , Cells, Cultured , Chickens , Dose-Response Relationship, Drug , Female , Fertility Agents, Female/metabolism , Fertility Agents, Female/pharmacology , Gonadotropin-Releasing Hormone/administration & dosage , Gonadotropin-Releasing Hormone/analogs & derivatives , Gonadotropin-Releasing Hormone/metabolism , Granulosa Cells/drug effects , Granulosa Cells/metabolism , Kinetics , Luteinizing Hormone/metabolism , Male , Ovary/chemistry , Ovary/cytology , Ovary/metabolism , Papio , Pituitary Gland/cytology , Pituitary Gland/metabolism , Progesterone/antagonists & inhibitors , Progesterone/metabolism , Tissue Extracts/metabolism
11.
Zhonghua Fu Chan Ke Za Zhi ; 37(2): 86-9, 2002 Feb.
Article in Chinese | MEDLINE | ID: mdl-11953071

ABSTRACT

OBJECTIVE: To assess the therapeutic effects of metformin in patients with polycystic ovary syndrome (PCOS) and clomiphene (CC) resistant cases. METHODS: Thirty one patients with PCOS, including 8 CC resistant cases were studied. Serum tissue-type plasminogen activator (tPA), plasminogen activator inhibitor type 1 (PAI-1), menstrual and reproductive hormone patterns, lipid and glucose metabolic parameters, bilateral ovarian volume, side effects were determined before and after oral administration of metformin 375 mg three times daily for 12 - 16 weeks. Metformin and CC were co-administered in CC resistant cases who had not restored their menstrual cycle after the treatment with metformin alone for investigating ovulation rate. In the remaining non-CC resistant metformin failure cases the dosage of metformin was incrersed to 500 mg three times daily for investigating menstrual cycle. RESULTS: After administration of metformin for 12 - 16 weeks, serum PAI-1, luteinizing hormone (LH)/follicle stimulating hormone (FSH) ratio, androstenedione, testosterone, low density liproprotein-cholesterol, total cholesterol, fasting insulin concentration and response to oral glucose tolerant test (OGTT), diastolic blood pressure decreased significantly, while FSH and estradiol levels increased, bilateral ovarian volume shrunk significantly (P < 0.05 - 0.01). Body mass index, waist hip ratio, LH, tPA, systolic blood pressure, prolactin, fasting glucose concentration and response to OGTT, high density liproprotein-cholesterol, apoliprotein A, apoliprotein B, triglycerides levels did not change significantly (P > 0.05). Nineteen out of thirty one cases (61%) had restoration of menstrual cycle, 2 became pregnant. In 6 CC resistant cases who had not restoration of menstrual cycle after the treatment with metformin, CC induced ovulation in 12/18 cycles or 5/6 cases and 2 pregnancies achieved. In others 6 metformin failure cases the dosage of metformin was increased to 500 mg three times daily, one restored menstrual cycle and became pregnant. CONCLUSIONS: Metformin may ameliorate the PAI-1, endocrine, metabolic profiles and menstrual abnormalities and improve the ovarian response to CC in CC resistant cases. Metformin provides a safe and effective approach to the treatment of PCOS.


Subject(s)
Clomiphene/therapeutic use , Hormones/blood , Metformin/therapeutic use , Plasminogen Activators/blood , Polycystic Ovary Syndrome/drug therapy , Adult , Androstenedione/blood , Blood Glucose/drug effects , Blood Glucose/metabolism , Cholesterol/blood , Cholesterol, LDL/blood , Drug Resistance , Estradiol/blood , Female , Fertility Agents, Female/metabolism , Fertility Agents, Female/therapeutic use , Follicle Stimulating Hormone/blood , Humans , Hypoglycemic Agents/therapeutic use , Insulin/blood , Luteinizing Hormone/blood , Plasminogen Activator Inhibitor 1/blood , Polycystic Ovary Syndrome/blood , Polycystic Ovary Syndrome/metabolism , Pregnancy , Testosterone/blood , Treatment Outcome
12.
Int J Gynaecol Obstet ; 75(1): 43-50, 2001 Oct.
Article in English | MEDLINE | ID: mdl-11597618

ABSTRACT

OBJECTIVES: To evaluate the clinical features, endocrine and metabolic profiles in clomiphene (CC) responders and non-responders with polycystic ovarian disease (PCOD), and to examine the effects of metformin (MTF) on the above parameters of CC resistance. METHODS: A prospective clinical trial was undertaken at the infertility division of a university teaching hospital. Forty-one CC responders were selected and their hormonal and clinical features were determined. Forty-one CC-resistant PCOD women were also selected and clinical features; metabolic and hormonal profiles before and after treatment with MTF 1500 mg/day for 6-8 weeks were evaluated. Women who failed to conceive were treated by CC while continuing to take MTF. RESULTS: CC responders had higher insulin levels while non-responders were hyperinsulinemic. Menstrual irregularities improved in 30%. Mean+/-S.D. area under curve of insulin decreased from 297.58+/-191.33 to 206+/-0.1 mIU/ml per min (P=0.005). Only 39.39% ovulated and 24.24% conceived. CONCLUSION: PCOD is associated with insulin resistance (IR) particularly in CC-resistant women. Insulin resistance and androgen levels are significantly higher in obese patients. MTF therapy improved hyperandrogenemia, IR, and pregnancy rate.


Subject(s)
Clomiphene/metabolism , Clomiphene/therapeutic use , Fertility Agents, Female/metabolism , Fertility Agents, Female/therapeutic use , Insulin Resistance/physiology , Metformin/metabolism , Metformin/therapeutic use , Polycystic Ovary Syndrome/drug therapy , Polycystic Ovary Syndrome/metabolism , Adult , Analysis of Variance , Blood Glucose/drug effects , Body Mass Index , Female , Gonadal Steroid Hormones/blood , Humans , Infertility, Female/drug therapy , Infertility, Female/metabolism , Insulin/blood , Obesity/metabolism , Prospective Studies , Regression Analysis
13.
Cancer ; 91(10): 1889-95, 2001 May 15.
Article in English | MEDLINE | ID: mdl-11346871

ABSTRACT

BACKGROUND: The degree of testicular damage resulting from primary treatment of prostate carcinoma by external beam radiation therapy (EBRT) to the prostate bed has not been determined. If significant testicular damage has occurred, the resulting endocrine changes may result in modified tumor behavior, contribute to postradiation impotence, and may aggravate other signs and symptoms of hypogonadism, potentially influencing a patient's choice of primary treatment for his tumor. METHOD: Three to eight years after primary treatment for localized prostate carcinoma, serologic evaluation for hypogonadism was undertaken in 33 men who had received EBRT and in 55 similar men who had received radical prostatectomy (RP). No subjects had developed recognized tumor recurrence, and none had undergone hormonal treatment since primary therapy. RESULTS: Among men of similar age, prior treatment with EBRT was associated with significantly more frequent hypogonadism than prior treatment with RP. In men with EBRT, total testosterone levels averaged 27.3% less, free testosterone levels 31.6% less, dihydrotestosterone levels 33.4% less, luteinizing hormone (LH) levels 52.7% greater, and follicle-stimulating hormone (FSH) levels 100% greater than those values in men who had prior treatment with RP. Differences between postradiation and postsurgical men in LH and FSH levels were most prominent in men older than 70 years. CONCLUSIONS: Three to eight years after primary treatment for prostate carcinoma, striking hormone differences were present between men who had received EBRT to the prostate bed and those with prior RP. These differences strongly suggested that prominent and permanent testicular damage was sustained during EBRT, frequently severe enough to cause hypogonadism.


Subject(s)
Hypogonadism/etiology , Prostatic Neoplasms/radiotherapy , Radiation Injuries/etiology , Testis/radiation effects , Aged , Aged, 80 and over , Dihydrotestosterone/blood , Estradiol/blood , Fertility Agents, Female/blood , Fertility Agents, Female/metabolism , Follicle Stimulating Hormone/blood , Follicle Stimulating Hormone/metabolism , Gonadotropin-Releasing Hormone/blood , Gonadotropin-Releasing Hormone/metabolism , Humans , Hypogonadism/blood , Luteinizing Hormone/blood , Luteinizing Hormone/metabolism , Male , Middle Aged , Orchiectomy , Prostatic Neoplasms/blood , Prostatic Neoplasms/pathology , Radiation Injuries/blood , Testis/pathology , Testosterone/blood
14.
Am J Med ; 111(8): 602-6, 2001 Dec 01.
Article in English | MEDLINE | ID: mdl-11755502

ABSTRACT

PURPOSE: Hirsute women with normal ovulatory menstrual function are often diagnosed as having idiopathic hirsutism. We prospectively evaluated 62 hirsute ovulatory women to determine if they had a subtle form of polycystic ovary syndrome, and if they exhibited any of the metabolic abnormalities commonly associated with classic polycystic ovary syndrome. METHODS: Baseline hormonal profiles, ovarian responses to gonadotropin-releasing hormone agonist, and ovarian morphology by ultrasound were compared in the hirsute women and two groups of ovulatory controls. RESULTS: Among 62 women, only 8 (13%) had normal androgen levels and were considered to have idiopathic hirsutism. Twenty-four (39%) had characteristic polycystic ovaries on ultrasound, an exaggerated response of 17-hydroxyprogesterone to leuprolide, or both, suggesting ovarian hyperandrogenism and the diagnosis of mild polycystic ovary syndrome. The remaining 30 women (48%) were considered to have unspecified hyperandrogenism. Age, body weight, and androgen level were similar among the hyperandrogenic subgroups. However, when compared with both normal and overweight controls and with patients with idiopathic hirsutism, the women who had mild polycystic ovary syndrome had higher fasting insulin levels [P < 0.01, mean (+/- SD) increase of 7 +/- 3 microU/mL], lower glucose-insulin ratios (P < 0.01, mean reduction of 3 +/- 1.5), higher low-density lipoprotein cholesterol levels (P < 0.05, mean increase of 26 +/- 10 mg/dL), and lower high-density lipoprotein (HDL) cholesterol levels (P < 0.01, mean reduction of 10 +/- 4 mg/dL). Compared with patients who had unspecified hyperandrogenism, these women also had higher fasting insulin levels (P < 0.05), lower glucose-insulin ratios (P < 0.05), and lower HDL cholesterol levels (P < 0.05). CONCLUSION: These data suggest that mild polycystic ovary syndrome is more common than idiopathic hirsutism, and it is also associated with subtle metabolic abnormalities.


Subject(s)
Hirsutism/complications , Hirsutism/metabolism , Menstrual Cycle/metabolism , Polycystic Ovary Syndrome/complications , Polycystic Ovary Syndrome/metabolism , Adult , Analysis of Variance , Androgens/blood , Blood Glucose/analysis , Body Mass Index , Cholesterol/blood , Female , Fertility Agents, Female/metabolism , Gonadal Steroid Hormones/blood , Hirsutism/diagnostic imaging , Humans , Insulin/blood , Leuprolide/metabolism , Polycystic Ovary Syndrome/diagnostic imaging , Prospective Studies , Triglycerides/blood , Ultrasonography
15.
AAPS PharmSciTech ; 1(1): E1, 2000 Feb 28.
Article in English | MEDLINE | ID: mdl-14727850

ABSTRACT

The primary objective of this study was to evaluate the effect of drug loading on the release of leuprolide acetate from an injectable polymeric implant, formed in situ, and efficacy of the released drug in suppressing serum testosterone levels in dogs for at least 90 days. An additional objective was to compare the optimum implant formulation with a commercial microsphere product. Evaluated implant formulations contained 45% w/w 75/25 poly (DL-lactide-co-glycolide) polymer having an intrinsic viscosity of 0.20 dL/g, dissolved in N-methyl-2-pyrrolidone. Irradiated polymer solution was mixed with leuprolide at different drug loads (3%, 4.5%, and 6% w/w) prior to subcutaneous administration to dogs. Dog serum was analyzed for testosterone (RIA) and leuprolide (LC/MS/MS) levels and comparisons within the three implant formulation groups were made. Varying the drug load did not significantly affect the release of leuprolide or efficacy of the implant formulation. Thus, the 6% w/w formulation with the smaller injection volume was selected for comparison with the commercial LUPRON Depot product, which was administered intramuscularly at a similar dosage. These comparisons of serum testosterone and leuprolide levels showed no significant difference in the pharmacologic efficacy even though drug levels were different at a number of points. This was mainly due to associated high standard deviations. Based on these studies, the 6% w/w leuprolide implant formulation was considered to be a suitable candidate for further development. Additional benefits of this system include its simple manufacturing and lower costs.


Subject(s)
Leuprolide/metabolism , Leuprolide/pharmacology , Polymers/chemistry , Prostheses and Implants , Animals , Delayed-Action Preparations/chemistry , Delayed-Action Preparations/metabolism , Delayed-Action Preparations/pharmacology , Dogs , Drug Implants/chemistry , Fertility Agents, Female/chemistry , Fertility Agents, Female/metabolism , Fertility Agents, Female/pharmacology , Leuprolide/blood , Leuprolide/chemistry , Male , Molecular Weight , Testosterone/blood
16.
Br J Pharmacol ; 121(1): 1-6, 1997 May.
Article in English | MEDLINE | ID: mdl-9146879

ABSTRACT

1. The sigma-drug binding site of guinea-pig liver is carried by a protein which shares significant amino acid sequence similarities with the yeast sterol C8-C7 isomerase (ERG2 protein). Pharmacologically-but not structurally-the sigma 1-site is also related to the emopamil binding protein, the mammalian sterol C8-C7 isomerase. We therefore investigated if sterol C8-C7 isomerase inhibitors are high affinity ligands for the (+)-[3H]-pentazocine labelled sigma 1-binding site. 2. Among the compounds which bound with high affinity to native hepatic and cerebral as well as to yeast expressed sigma 1-binding sites were the agricultural fungicide fenpropimorph (Ki 0.005 nM), the antihypocholesterinaemic drugs triparanol (Ki 7.0 nM), AY-9944 (Ki, 0.46 nM) and MDL28,815 (Ki 0.16 nM), the enantiomers of the ovulation inducer clomiphene (Ki 5.5 and 12 nM, respectively) and the antioestrogene tamoxifen (Ki 26 nM). 3. Except for tamoxifen these affinities are essentially identical with those for the [3H]-ifenprodil labelled sterol C8-C7 isomerase of S. cerevisiae. This demonstrates that sigma 1-binding protein and yeast isomerase are not only structurally but also pharmacologically related. Because of its affiliations with yeast and mammalian sterol isomerases we propose that the sigma 1-binding site is localized on a sterol isomerase related protein, involved in postsqualene sterol biosynthesis.


Subject(s)
Brain/metabolism , Microsomes, Liver/metabolism , Receptors, sigma/metabolism , Steroid Isomerases/metabolism , Animals , Binding Sites , Brain/drug effects , Calcium Channel Blockers/metabolism , Clomiphene/metabolism , Clomiphene/pharmacology , Estrogen Antagonists/metabolism , Estrogen Antagonists/pharmacology , Excitatory Amino Acid Antagonists/metabolism , Fertility Agents, Female/metabolism , Fertility Agents, Female/pharmacology , Fungicides, Industrial/metabolism , Fungicides, Industrial/toxicity , Guinea Pigs , Hypolipidemic Agents/metabolism , Hypolipidemic Agents/pharmacology , Isoquinolines/metabolism , Isoquinolines/pharmacology , Isotope Labeling , Microsomes/metabolism , Microsomes, Liver/drug effects , Morpholines/metabolism , Morpholines/toxicity , Pentazocine/metabolism , Piperidines/metabolism , Receptors, sigma/drug effects , Saccharomyces cerevisiae/enzymology , Saccharomyces cerevisiae/metabolism , Stereoisomerism , Steroid Isomerases/antagonists & inhibitors , Tamoxifen/metabolism , Tamoxifen/pharmacology , Triparanol/metabolism , Triparanol/pharmacology , Verapamil/analogs & derivatives , Verapamil/metabolism , trans-1,4-Bis(2-chlorobenzaminomethyl)cyclohexane Dihydrochloride/metabolism , trans-1,4-Bis(2-chlorobenzaminomethyl)cyclohexane Dihydrochloride/pharmacology
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