FEMALE INFERTILITY: Ovulatory Disorders

Fertil Steril 2002 Feb;77(2):209-15
Comment in:
Fertil Steril. 2002 Sep;78(3):653-4; discussion 654-5.
Strategies for the use of insulin-sensitizing drugs to treat infertility in women with polycystic ovary syndrome. Nestler JE, Stovall D, Akhter N, Iuorno MJ, Jakubowicz DJ.
Department of Internal Medicine, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298-0111, USA. nestler@hsc.vcu.edu OBJECTIVE: Insulin resistance and its compensatory hyperinsulinemia play a key pathogenic role in the infertility of the polycystic ovary syndrome. Numerous studies indicate that insulin-sensitizing drugs can be used to enhance spontaneous ovulation and the induction of ovulation in the syndrome. The aim of this review is to summarize the studies in which insulin-sensitizing drugs were used to increase ovulation rate or improve fertility in women with the PCOS and to translate the information into practical guidelines for the use of these drugs by reproductive endocrinologists. DESIGN: Review and critique of studies in which an insulin-sensitizing drug was used to increase ovulation rate or improve infertility in women with the polycystic ovary syndrome. MAIN OUTCOME MEASURE(S): Ovulation rate and pregnancy rate. RESULT(S): Studies have demonstrated that insulin-sensitizing drugs can increase spontaneous ovulation, enhance the induction of ovulation with clomiphene citrate, and increase clinical pregnancy rates. CONCLUSION(S): An algorithmic approach is provided for the use of insulin-sensitizing drugs to treat the anovulation and infertility of women with the polycystic ovary syndrome.

 

Hum Reprod 2001 Dec;16(12):2610-5
Endometrial cavity fluid is associated with poor ovarian response and increased cancellation rates in ART cycles.
Levi AJ, Segars JH, Miller BT, Leondires MP.
Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA. BACKGROUND: Endometrial cavity fluid (ECF) is occasionally observed during assisted reproductive technology (ART) cycles. However, few reports have described its prevalence or significance. METHODS AND RESULTS: We examined the relationships between ECF, clinical pregnancy rate (CPR), tubal factor infertility and ultrasound-visible (USV) hydrosalpinges. In 843 ART cycles involving 721 patients, ECF was observed during stimulation in 57 cycles and after human chorionic gonadotrophin (HCG) administration in 12 cycles, with an overall incidence of 8.2% (69/843). When ECF was observed during stimulation, the cancellation rate due to poor ovarian response was significantly higher (29.8 versus 16.9%, P <0.05) and the CPR per started cycle was significantly lower (26.3 versus 42.4%, P <0.05) than cycles without ECF. When ECF developed after HCG administration, the CPR was similar compared with that of the group for which ECF was not observed. In the 327 cycles involving tubal factor infertility patients, USV hydrosalpinges were noted in 71 cycles (71/327; 21.7%), and ECF developed in five of those cycles (5/71; 7.0%). A total of 27 cycles during which ECF developed (27/57, 47.4%) involved non-tubal factor patients. CONCLUSIONS: ECF during stimulation was associated with increased cancellation rates and lower CPRs per started cycle, and was not associated with USV hydrosalpinges. Furthermore, ECF observed after HCG administration did not impact CPR and may represent a different clinical entity.

 

 

Niger J Med 2001 Apr-Jun;10(2):85-90
Anovulatory infertility: a report of four cases and literature review. Anate M, Olatinwo AW. Department of Obstetrics and Gynaecology, University of Ilorin Teaching Hospital, Ilorin. Four cases of anovulatory/dysovulatory infertility encountered in Ilorin, Nigeria are presented and the literature extensively reviewed on the up-to-date management of this aspect of infertility. All the patients had bilateral tubal patency on hysterosalpingography (HSG) and their husbands had normal seminal fluid analysis. The first case, 30 years of age, had hyperprolactinaemia with galactorrhoea, treated with bromocriptine given 2.5 mg twice daily. Another case, aged 27 years, had polycystic ovarian syndrome with hyperprolactinaemia but no galactorrhea This was treated with clomiphene citrate 100 mg daily. The third case, 34 years old, had hypothyroidism with hyperprolactinaemia and galactorrhea and was treated with thyroxine. The last case, aged 32 years, had hyperprolactinaemia and was treated with bromocriptine and clomiphene citrate. None of the patients had demonstrable pituitary adenoma. After the appropriate treatment, ovulatory menses were restored in all the patients; two have been pregnant, while the other two have not yet achieved pregnancy but have having regular ovulatory menses. All the patients are Nigerians.

 

 

Mol Cell Endocrinol 2001 Nov 26;184(1-2):87-93
Polycystic ovary syndrome: the new millenium. Legro RS.
Department of Obstetrics and Gynecology, Pennsylvania State University College of Medicine, M.S. Hershey Medical Center, PO Box 850, Hershey, PA 17033, USA. rsl1@psu.edu Our understanding of Polycystic Ovary Syndrome (PCOS) has been hampered by varying diagnostic criteria, and ignorance of the etiology of the syndrome. PCOS women are uniquely insulin resistant and obesity aggravates this underlying predisposition to insulin resistance. Diagnostic criteria which focus on hyperandrogenism and/or menstrual irregularity are more likely to identify insulin resistant women, than such criteria as abnormal gonadotropin secretion or ovarian morphology. The lack of a clear etiologic mechanism to the syndrome has led to a multitude of symptom-oriented treatments with few therapies improving all aspects of the endocrine syndrome of PCOS. Improving insulin sensitivity has become established as a baseline treatment strategy in PCOS. There are, however, few randomized controlled trials of adequate power to provide an evidence based guide to treatment in PCOS.

 

 

Hum Reprod 2001 Oct;16(10):2073-8
Follicular fluid concentration of leukaemia inhibitory factor is decreased among women with polycystic ovarian syndrome during assisted reproduction cycles.
Ledee-Bataille N, Lapree-Delage G, Taupin JL, Dubanchet S, Taieb J, Moreau JF, Chaouat G.
Service de Gynecologie-Obstetrique et Medecine de la Reproduction, Hopital Antoine Beclere, 157 Rue de la Porte de Trivaux, 92140 Clamart, France. Ledeenathalie@aol.com BACKGROUND: The possibility that a specific cytokine profile could be detected in the ovaries of patients with polycystic ovarian syndrome (PCOS) was investigated. METHOD: Enzyme-linked immunosorbent assay (ELISA) or bioassays were used to assess the concentrations of leukaemia inhibitory factor (LIF), tumour necrosis factor, interleukin 11, gamma interferon, progesterone and oestradiol in follicular fluids from preovulatory follicles collected after ovarian stimulation from 15 PCOS patients, 15 infertile control patients with regular cycles, and 8 oocyte donors. RESULTS: LIF and progesterone concentrations were significantly lower in the follicular fluid of PCOS patients (LIF median: 265 pg/ml) compared with controls (LIF median: 816 pg/ml); LIF and progesterone follicular fluid concentrations were correlated (r = 0.720, P = 0.0001). The LH/FSH ratio was negatively correlated with LIF concentrations (r = - 0.714, P = 0.0075). Although the PCOS and control patients did not differ significantly in age, ovarian reserve or IVF indication, the implantation rate was significantly lower among the women with PCOS (IR = 9 versus 21%, P = < 0.01). CONCLUSION: The specific cytokine profile of the PCOS patients is probably related to the lower implantation rate since follicular fluid LIF appears to function as an embryotrophic agent.

 

Br J Clin Pharmacol 2002 May;53(5):469-73
Metformin does not enhance ovulation induction in clomiphene resistant polycystic ovary syndrome in clinical practice.
Sturrock ND, Lannon B, Fay TN.
Department of Endocrinology, Nottingham City Hospital NHS Trust, Hucknall Road, UK. nsturroc@ncht.trent.nhs.uk
AIMS: To determine whether metformin pretreatment has beneficial effects in clomiphene resistant infertile women with polycystic ovary syndrome (PCOS) in an infertility clinic. METHODS: This was a randomized placebo controlled double-blind crossover study of 3 months metformin (1500 mg day-1)/placebo, followed by 3 months metformin/placebo together with clomiphene (50-100 mg for 5 days) for three cycles in clomiphene resistant women with PCOS. The primary outcomes were restoration of spontaneous menses, ovulation induction (spontaneous or clomiphene induced) and pregnancy. Secondary endpoints were changes in biochemical parameters related to androgens and insulin. RESULTS: Twelve women completed the metformin arm and 14 the placebo arm. Spontaneous menstruation resumed in five metformin treated patients and in six placebo treated women, P=0.63. No women given metformin spontaneously ovulated, although one patient given placebo did, P=0.30. There was no difference in the efficacy of clomiphene between the two groups with ovulation being induced in five (out of 12) metformin treated women and four (out of 14) placebo treated women, P=0.63. Pregnancy occurred in three (out of 12) women given metformin and two (out of 14) women given placebo, P=0.59. CONCLUSIONS: Metformin is not always beneficial when given to clomiphene resistant infertile women with PCOS in clinical practice.

J Reprod Med 2001 Aug;46(8):765-8
Hepatic dysfunction associated with moderate ovarian hyperstimulation syndrome. A case report. Elter K, Scoccia B, Nelson LR.
Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology,
University of Illinois College of Medicine, Chicago, USA. BACKGROUND: Liver dysfunction is a rare complication of severe ovarian hyperstimulation syndrome (OHSS). Based on a MEDLINE search from 1966 to September 2000, we report the second case of liver dysfunction associated with moderate OHSS. In addition, this is the first report of moderate OHSS with serum progesterone levels during the first trimester of pregnancy higher than the upper limit of normal for a third-trimester gestation. CASE: A 33-year-old nulligravida with a history of infertility had previously undergone three failed cycles of assisted reproduction. During her fourth attempt at in vitro fertilization and intracytoplasmic sperm injection, she developed moderate OHSS 11 days after embryo transfer. She was managed on an outpatient basis. Her serum progesterone and liver enzyme levels were significantly elevated, as is unusual for the moderate picture of OHSS in this patient. CONCLUSION: Hepatic dysfunction is not limited to the severe forms of OHSS. Liver function should be analyzed even in moderate cases. Further study is needed to understand the role of elevated liver function tests and serum progesterone in the pathogenesis of OHSS.

 

 

Curr Opin Obstet Gynecol 2002 Jun;14(3):265-74
Is luteinizing hormone needed for optimal ovulation induction? Balasch J, Fabregues F.
Clinical Institute of Gynecology, Obstetrics and Neonatology, Faculty of Medicine, University of Barcelona, Hospital Clinic-Institut d'Investigacions Biomediques August Pi I Sunyer (IDIBAPS), Barcelona, Spain. jbalasch@medicina.ub.es The role of luteinizing hormone in the natural menstrual cycle is not disputed. There are, however, a variety of opinions regarding the potential role of exogenous luteinizing hormone in ovulation induction and whether it is actually needed. The recent introduction into clinical practice of recombinant gonadotropins has been paralleled by recent advances in the knowledge of the endocrine and paracrine mechanisms that regulate human folliculogenesis. On this basis, this review analyses whether or not all patients need luteinizing hormone for follicular growth stimulation. In addition, new opportunities for improved treatment are considered as a result of the availability of recombinant human luteinizing hormone both in patients with ovulatory disorders and those undergoing multiple follicular development for assisted reproduction.

 

 

Obstet Gynecol 2002 Feb;99(2):347-58
ACOG Practice Bulletin. Clinical management guidelines for obstetrician-gynecologists number 34, February 2002. Management of infertility caused by ovulatory dysfunction. American College of Obstetricians and Gynecologists.
ACOG Committee on Practice Bulletins-Gynecology. Approximately 20% of infertile women have ovulatory disorders. In infertile women with ovulatory disorders, the cause of anovulation will guide the selection of an appropriate treatment plan. Advances in reproductive endocrinology allow the generalist obstetrician-gynecologist to provide treatment that results in successful ovulatory stimulation and pregnancy in most women with ovulatory disorders. Cochrane Database Syst Rev 2000;(3):CD000057

 

 

Update of:
Cochrane Database Syst Rev. 2000;(2):CD000057.
Clomiphene citrate for unexplained subfertility in women. Hughes E, Collins J, Vandekerckhove P.
Rm HSC-4F7, Department of Obstetrics and Gynaecology, McMaster University, 1200 Main St West, Hamilton, Ontario, Canada, L8N 3Z5. hughese@fhs.csu.mcmaster.ca
BACKGROUND: The effectiveness of clomiphene citrate has been clearly demonstrated in the treatment of sub-fertility associated with oligo-ovulation. The multiple pregnancy rate associated with clomiphene, however, is elevated at approximately 10%. Additional side effects associated with clomiphene use also include hot flashes, mood swings, headaches and visual disturbances. A variety of publications have raised the question of increased ovarian cancer risks associated with clomiphene use. Understanding the effectiveness of clomiphene in this patient group is therefore, extremely important. OBJECTIVES: To determine the effectiveness of clomiphene citrate given to women with unexplained subfertility, in a dose range of 50-250 mg for up to 10 days. The primary outcome was clinical pregnancy. MAIN RESULTS: Clomiphene appeared to be superior to no treatment or placebo. The common odds ratios for clinical pregnancy per patient and per treatment cycle were 2.37 (1.22-4.62) and 2.5 (1.35-4.62) respectively. Although there was some clinical heterogeneity between studies, the results were statistically homogeneous (p>0.1). These data suggest statistically and clinically significant improvement in pregnancy rate following clomiphene citrate in women with unexplained infertility. REVIEWER'S CONCLUSIONS: Although the absolute treatment effect is small, given the low cost and ease of administration, clomiphene citrate appears to be a sensible first choice treatment for women with unexplained infertility. However, in making this treatment choice, concerns of long-term use and ovarian cancer risk, multiple pregnancy risk and minor symptoms should be discussed. Given the extensive use of clomiphene in ovulatory women and recent concerns associated with long term use, a definitive trial with adequate power is warranted to establish effectiveness in women with unexplained subfertility.

 

 

Fertil Steril 1999 Jan;71(1):96-101
Increased prevalence of luteinizing hormone beta-subunit variant in patients with premature ovarian failure.
Takahashi K, Ozaki T, Okada M, Kurioka H, Kanasaki H, Miyazaki K.
Department of Obstetrics and Gynecology, Shimane Medical University, Izumo, Japan. taka27@shimane-med.ac.jp
OBJECTIVE: To evaluate the significance of an LH variant with a mutant beta-subunit (Trp8 to Arg8 and Ile15 to Thr15) in gynecologic disease, including infertility. DESIGN: Clinical study. SETTING: Department of Obstetrics and Gynecology, Shimane Medical University Hospital, Izumo, Japan. PATIENT(S): Two hundred forty-five Japanese women with endocrine disorders and/or gynecologic disease and 153 healthy, nonpregnant, fertile Japanese women. INTERVENTION(S): A blood sample was collected. MAIN OUTCOME MEASURE(S): The ratio of LH values from the SPAC-S and Immulyze assays (LH ratio: SPAC-S LH/Immulyze LH) was used to determine variant (< or =0.5) or wild-type (>0.5) LH status according to a demonstrated relation between the ratio and the sequence of the LH beta-subunit gene. RESULT(S): The LH ratio was lower (0.80+/-0.31) in the 245 patients than in the controls (1.00+/-0.38), and the variant was more frequent in the patients (18.4%) than in the controls (8.5%). We found no difference in the frequency of the variant between infertile and fertile patients. The prevalence of infertility did not differ between patients with variant LH and patients with normal LH. Ovulatory disorders, hyperprolactinemia, premature ovarian failure, menstrual disorders, and luteal insufficiency were significantly more frequent in patients with the variant. CONCLUSION(S): Variant LH may contribute to female reproductive disorders, including infertility and premature ovarian failure.

 

 

Hum Reprod 1998 Aug;13(8):2092-7
Female patients with cystic fibrosis suffer from reproductive endocrinological disorders despite good clinical status.
Johannesson M, Landgren BM, Csemiczky G, Hjelte L, Gottlieb C.
Stockholm CF Center, Department of Pediatrics, Huddinge Hospital, Sweden. Ten women with cystic fibrosis (CF) were evaluated with regard to hormonal profiles during a natural and a clomiphene citrate (CC) stimulated cycle. Five of the women were found to be anovulatory during a natural cycle. All women except one did respond with ovulation to CC stimulation indicating adequate ovarian response. Neither did they show increased follicle-stimulating hormone (FSH) concentrations on day 10 after CC treatment confirming normal ovarian reserve. Clinically the anovulatory women differed from the ovulating in two aspects: more profound essential fatty acid deficiency (EFAD) and higher peak/basal insulin response during an oral glucose tolerance test. The anovulatory women had significantly lower luteal oestradiol and progesterone but higher total testosterone concentrations when compared to healthy controls and the ovulatory CF women. The pathological insulin response and high testosterone concentrations resemble those seen in women with polycystic ovarian (PCO) syndrome. However, the CF patients in our study had normal ovaries, as deduced from ultrasound examination and normal luteinizing hormone (LH)/FSH ratio. It is suggested that EFAD as well as hypersecretion of insulin may be of importance for the observed ovarian dysfunction. Further studies are needed to evaluate the relation between ovulatory mechanisms and EFAD in CF women as well as studies to compare anovulatory CF women with women with PCO syndrome.

 

 

Acta Obstet Gynecol Scand 2000 Aug;79(8):687-92
Child rate, pregnancy outcome and ovarian function in females with classical 21-hydroxylase deficiency.
Jaaskelainen J, Hippelainen M, Kiekara O, Voutilainen R.
Department of Pediatrics, Kuopio University Hospital, Finland. BACKGROUND: Ovulatory disorders and decreased fertility rates have been found in females with classical 21-hydroxylase deficiency (21-OHD). We analyzed the pregnancies of 29 females with classical 21-hydroxylase deficiency and examined 16 of these women in a cross-sectional study. METHODS: The child rate of the 29 patients was compared with that in the general Finnish female population with equal age distribution.The cross-sectional study of the 16 patients included a standardized questionnaire, clinical examination, ultrasonography of the internal genitalia, basal measurements of serum steroids, sex hormone binding globulin, PRL, gonadotropins and plasma ACTH. RESULTS: The child rate was significantly lower than that in the general population (0.34 vs 0.91; p<0.001). A total of 13 pregnancies could be registered. From these pregnancies, ten healthy children were born, all for females with a simple virilizing disease. None of the nine females with salt wasting 21-OHD had any children or had sought treatment for infertility. In the cross-sectional study, females with regular menses (5/16; 31%) had well controlled adrenal androgen secretion and they had normal serum progesterone concentrations whereas the females with irregular menses (11/16; 69%) were often undersubstituted and presented with high serum progesterone concentration in the follicular phase. Polycystic ovaries could not be detected in any of these patients. CONCLUSIONS: Females with simple virilizing 21-OHD often have irregular menses but their final prognosis for fertility seems to be better than previously reported. On the contrary, our study confirms the extremely low child rate in the salt wasting group.

 

 

Impact of metformin therapy on ovarian stimulation and outcome in 'coasted' patients with polycystic ovary syndrome undergoing in-vitro fertilization. Stadtmauer LA, Toma SK, Riehl RM, Talbert LM.
Jones Institute for Reproductive Medicine, 601 Colley Avenue, Norfolk, VA 23507, USA; e-mail: Stadtmla@evms.edu
This study was designed to determine if metformin therapy improves ovarian stimulation and IVF outcomes in coasted patients with clomiphene-resistant polycystic ovarian syndrome (PCOS). A retrospective#10; data analysis was performed on women with clomiphene citrate-resistant PCOS treated with or without metformin, who underwent 72 cycles of IVF-embryo transfer with intracytoplasmic sperm injection (ICSI).#10; In 59 cycles, patients were coasted to allow oestradiol concentrations to drop before human chorionic gonadotrophin administration. In patients undergoing coasting, the outcome of IVF with ICSI was compared#10; in those who were treated and untreated. In patients treated with metformin, follicular fluid concentrations of testosterone and insulin were significantly lower (60.5 +/- 5 versus 79.1 +/- 6#10; ng/dl; P < 0.05 and 18 +/- 2.5 versus 22 +/- 2.4 &mgr;IU/ml; P < 0.05 respectively), and the mean number of oocytes retrieved (22.3 +/- 2.4 versus 19.7 +/- 1.6) did not differ.#10; The metformin-treated group showed an increase in the mean number of mature oocytes, oocytes fertilized and cleaving embryos (4-cell or greater by 72 h). However, in the group of patients undergoing coasting,#10; maximum oestradiol concentrations and number of days of coasting were all lower in the metformin-treated group with increased clinical pregnancy rates (71 versus 30%, P < 0.05). Therefore, metformin#10; use appears beneficial in improving IVF outcomes in clomiphene citrate-resistant PCOS patients. #10;