Conventional dose intravenous pulsatile GnRH therapy does not induce ovulation in polycystic ovarian disease

The value of pulsatile GnRH therapy for induction of ovulation in patients with polycystic ovarian disease remains unclear. Intravenous pulsatile GnRH therapy was administered to a defined group of 5 patients with polycystic ovarian disease; all were infertile, had an LH:FSH ratio of greater than 2:1 on two or more occasions, and had multiple cysts on ovarian ultrasonography. All had failed to respond to clomiphene citrate. The 5 patients received increasing doses of GnRH (5-40 micrograms/pulse) continuously for up to 6 weeks. The response was evaluated by serial hormone levels and ovarian ultrasonography. During nine treatment periods no patient ovulated, and in only one did the LH:FSH ratio revert to normal. Four patients have subsequently had wedge resection of the ovaries and in each case the diagnosis of polycystic ovarian disease was confirmed. Pulsatile GnRH therapy was of no value in the management of this group of infertile patients with strictly defined polycystic ovarian disease.     

The effect of leuprolide acetate on ovulation induction with human menopausal gonadotropins in polycystic ovary syndrome

The use of exogenous gonadotropins for treatment of clomiphene-resistant chronic anovulation in women with the polycystic ovary syndrome (PCO) is hazardous and often ineffective, possibly because of the abnormal endogenous gonadotropin secretion characteristic of PCO. We evaluated the effect of leuprolide acetate, a long-acting GnRH agonist, on serum gonadotropin and sex steroid concentrations before and during human menopausal gonadotropin (hMG) induction of ovulation in women with PCO. In this controlled prospective randomized study, leuprolide was administered daily for 4 weeks, followed by concomitant hMG administration. Gonadotropin and steroid hormone concentrations were compared with those during ovulation induction cycles in women with PCO receiving hMG only. Daily administration of leuprolide for 4 weeks resulted in significantly decreased serum LH, estradiol, and testosterone concentrations, but no change in serum progesterone, FSH, and dehydroepiandrosterone sulfate. Compared to ovulation induction using hMG alone, leuprolide administration before and during hMG treatment prevented preovulatory rises in serum LH and P concentrations, while having no effect on serum FSH, testosterone, estradiol, and dehydroepiandrosterone sulfate. We conclude that leuprolide administered to women with PCO decreases gonadal steroid production and is capable of preventing premature luteinization during hMG induction of ovulation.     

Gonadotropin-releasing hormone (GnRH) analog suppression renders polycystic ovarian disease patients more susceptible to ovulation induction with pulsatile GnRH

Pulsatile GnRH administration consistently restores normal reproductive hormone levels and ovulation in women with hypogonadotropic hypogonadism, but is less effective in those with polycystic ovarian disease (PCOD). We pharmacologically created a hypogonadotropic condition with a GnRH analog (GnRH-A) in six women with PCOD to investigate the role of deranged gonadotropin secretion in PCOD and to improve the response to pulsatile GnRH ovulation induction. Before GnRH and GnRH-A treatment the women with PCOD had increased LH pulse frequency [one pulse every 55 +/- 2 (+/- SE) min; P less than 0.05] and LH pulse amplitude (10.9 +/- 1.4 U/L; P less than 0.05) compared to normal women in the follicular phase of their menstrual cycle. Each PCOD woman completed one cycle of pulsatile GnRH administration for ovulation induction before (pre-A cycles; n = 6) and one or two cycles after (post-A cycles; n = 9) GnRH-A administration [D-Ser(tBu)6-Des,Gly10-GnRH; 300 micrograms, sc, twice daily for 8 weeks]. Pulsatile GnRH (5 micrograms/bolus) was given at 60-min intervals using a Zyklomat pump. Daily blood samples were drawn during the pulsatile GnRH ovulation induction cycles for the determination of serum LH, FSH, estradiol (E2), progesterone, and testosterone, and pelvic ultrasonography was done at 1- to 4-day intervals. Mean (+/- SE) serum LH levels were elevated during the pre-A cycle (49.2 +/- 3.1 IU/L) and decreased to normal levels during the post-A cycles (19.6 +/- 1.4 IU/L; P less than 0.0001). Mean testosterone concentrations were lower during the post-A cycles [88 +/- 2 ng/dL (3.1 +/- 0.1 nmol/L)] than during the pre-A cycles [122 +/- 3 ng/dL (4.2 +/- 0.1 nmol/L); P less than 0.0001]. In the follicular phase of the post-A cycles E2 levels were significantly lower [81 +/- 5 pg/mL (300 +/- 20 pmol/L) vs. 133 +/- 14 pg/mL (490 +/- 50 pmol/L); P less than 0.0001], preovulatory ovarian volume was smaller (24.6 +/- 2.0 vs. 31.4 +/- 2.4 cm3; P less than 0.01), and the FSH to LH ratio was higher (0.56 +/- 0.03 vs. 0.16 +/- 0.01) than in the pre-A cycle, suggesting more appropriate function of the pituitary-gonadal axis. Excessive LH and E2 responses to pulsatile GnRH administration in the early follicular phase of the pre-A cycle were abolished in the post-A cycles.(ABSTRACT TRUNCATED AT 400 WORDS)     

Successful use of pulsatile gonadotropin-releasing hormone (GnRH) for ovulation induction and pregnancy in a patient with GnRH receptor mutations

GnRH receptor mutations have recently been identified in a small number of familial cases of nonanosmic hypogonadotropic hypogonadism. In the present report we studied a kindred in which two sisters with primary amenorrhea were affected with GnRH deficiency due to a compound heterozygote mutation (Gln(106)Arg, Arg(262)Gln) and performed extensive phenotyping studies. Baseline patterns of gonadotropin secretion and gonadotropin responsiveness to exogenous pulsatile GnRH were examined in the proband. Low amplitude pulses of both LH and free alpha-subunit (FAS) were detected during 24 h of every 10 min blood sampling. The proband then received exogenous pulsatile GnRH i.v. for ovulation induction, and daily blood samples for gonadotropins and sex steroids were monitored. At the conventional GnRH replacement dose for women with hypogonadotropic hypogonadism (75 ng/kg), no follicular development occurred. At a GnRH dose of 100 ng/kg, the level and pattern of gonadotropin secretion more closely mimicked the follicular phase of normal women; a single dominant follicle was recruited, and an endogenous LH surge was elicited. However, the luteal phase was inadequate, as assessed by progesterone levels. At a GnRH dose of 250 ng/kg, the gonadotropin and sex steroid dynamics reproduced those of normal ovulatory women in both the follicular and luteal phases, and the proband conceived. The FAS responses to both conventional and high dose GnRH were within the normal range. The following conclusions were made: 1) Increased doses of GnRH may be used effectively for ovulation induction in some patients with GnRH receptor mutations. 2) Higher doses of GnRH are required for normal luteal phase dynamics than for normal follicular phase function. 3) Hypersecretion of FAS in response to exogenous GnRH, which is a feature of congenital hypogonadotropic hypogonadism, was not seen in this patient with a GnRH receptor mutation.     

Induction of ovulation by Sairei-to for polycystic ovary syndrome patients.

In anovulatory patients ovulation is usually induced by clomiphene citrate (CC) or gonadotropin therapy, but in the case of polycystic ovary syndrome (PCOS), diagnosed by the presence of several micropolycysts in the ovaries and a high LH/FSH ratio in the serum, CC is only minimally effective, and side effects are often a problem with gonadotropin therapy. In the present study we administered a Chinese herbal medicine Sairei-to which appears to have a steroidal effect in anovulatory PCOS patients. As a result of the treatment, serum LH and the LH/FSH ratio significantly decreased (P<0.01) and the ovulatory rate was 70.6%. Serum testosterone levels were within normal limits before the treatment, and did not significantly change during the treatment. Sairei-to may therefore be useful for the treatment of anovulation in PCOS patients.     

Metformin administration improves leukocyte count in women with polycystic ovary syndrome: a 6-month prospective study

INTRODUCTION: Polycystic ovary syndrome (PCOS) is a common disorder associated with a wide range of endocrine and metabolic abnormalities. Low-grade chronic inflammation is a related complication recently observed in PCOS. Increased white blood cell (WBC) count was previously reported in PCOS women. OBJECTIVE: To evaluate the effects of six months metformin administration on WBC count in PCOS women. PATIENTS AND METHODS: Fifty normal-weight PCOS women without additional metabolic or cardiovascular diseases were enrolled and treated with metformin (850 mg twice daily) for 6 months in a prospective baseline-controlled clinical study. At baseline and after treatment, WBC count and C-reactive protein (CRP) were evaluated in each patient. The whole hormonal profile, serum insulin and glucose levels (at fasting and during a 75 g 2-h oral glucose tolerance test), serum lipid profile were also assessed. RESULTS: A significant difference was observed in WBC count (7050 +/- 552 vs 6080 +/- 577 cell/mm(3) +/- s.d., P<0.001) and CRP levels (1.8 +/- 0.9 vs 1.1 +/- 0.6 mg/l +/- s.d., P<0.001) after metformin treatment in comparison with baseline values. SHBG levels and the free androgen index also changed significantly (P<0.001). Finally, high-density lipoproteins and the area under curve for glucose/area under curve for insulin ratio also significantly increased (P<0.001), whereas low-density lipoproteins and area under curve for insulin were significantly reduced (P<0.001). No other change was found in any of the biochemical parameters evaluated. CONCLUSION: A six-month course of metformin reduces WBC count in PCOS women.     

Risk factors for preeclampsia in infertile Chinese women with polycystic ovary syndrome: A prospective cohort study

To explore preconception risk factors for preeclampsia (PE) in women with polycystic ovary syndrome (PCOS), a prospective cohort study was conducted in 92 infertile Chinese women with PCOS who had a singleton pregnancy by ovulation induction and were followed up for 6 weeks after delivery. The patients underwent assessment of physical, endocrine, and metabolic features before ovulation induction. Fifteen (16.3%) patients were diagnosed with PE. Logistic regression analysis showed that preconception sex hormone–binding globulin (SHBG), insulin level at 120 minutes, and body mass index were three independent risk factors for PE (odds ratio [OR], 0.981; 95% confidence interval [CI], 0.964–0.998 [P=.027]; OR, 1.011; 95% CI, 1.000–1.021 [P=.048]; and OR, 1.249; 95% CI, 0.992–1.572 [P=.059], respectively). Receiver operator characteristic analysis indicated the risk value of prepregnancy SHBG, insulin level at 120 minutes, and body mass index (area under the curve=.788, .686, and .697, respectively). Preconception low SHBG levels, overweight/obesity, and hyperinsulinism might be correlated with the subsequent development of PE in patients with PCOS.     

Drospirenone for the treatment of hirsute women with polycystic ovary syndrome: a clinical, endocrinological, metabolic pilot study

The aim of this study was to investigate the effects of the new estro-progestinic containing the antimineralcorticoid progestogen drospirenone (DRSP) in women with polycystic ovary syndrome (PCOS). Fifteen hirsute PCOS patients were treated with 30 microg ethinyl estradiol plus 3 mg DRSP for 12 cycles. Ultrasonographic pelvic exams, evaluation of hirsutism scores, and hormonal and lipid profile assays were performed at baseline and after three, six, and 12 cycles of treatment. An oral glucose tolerance test and euglycemic hyperinsulinemic clamp were also performed, except at the third cycle. The treatment was well tolerated, and all women attained satisfactory cycle control. Hirsutism significantly improved from the sixth cycle onward. Body weight and fat distribution as well as blood pressure remained stable throughout the treatment. Plasma levels of LH, testosterone, SHBG, and, consequently, the free androgen index significantly fell from the third cycle on. Dehydroepiandrosterone sulfate and 17-hydroxyprogesterone significantly decreased after six cycles. The treatment did not affect glycoinsulinemic homeostasis. A trend toward an increase was seen for total cholesterol, triglycerides, and high- and low-density lipoproteins (HDL and LDL) plasma concentrations, although all parameters remained within the normal range. No modifications in total cholesterol/HDL and HDL/LDL ratios were induced by the therapy. The ethinyl estradiol/DRSP combination seems to be effective in ameliorating clinical and hormonal features of PCOS.     

Heritability of polycystic ovary syndrome in a Dutch twin-family study

BACKGROUND: Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders among women of reproductive age. There is evidence for a genetic component in PCOS based on familial clustering of cases. OBJECTIVE: In the present study, the heritability of PCOS was estimated. DESIGN/PARTICIPANTS: Data from 1332 monozygotic twins (genetically identical) and 1873 dizygotic twins/singleton sisters of twins (who share on average 50% of their segregating genes) registered with The Netherlands Twin Register were used. PCOS was defined as less than nine menstrual cycles and acne or hirsutism in agreement with the 2003 Rotterdam consensus. RESULTS: Results point to a strong contribution of familial factors to PCOS. The resemblance in monozygotic twin sisters (tetrachoric correlation 0.71) for PCOS was about twice as large as in dizygotic twin and other sisters (tetrachoric correlation 0.38). Univariate analyses point to strong contributions of genetic factors to the variance in PCOS. Next, a trivariate genetic analysis of oligomenorrhea, acne, and hirsutism was carried out. This analysis confirmed that the familial component in PCOS is due to genetic factors. CONCLUSIONS: This study demonstrated a large influence of genetic factors to the pathogenesis of PCOS, justifying the search for susceptibility genes.     

The effect of metformin on hirsutism in polycystic ovary syndrome

OBJECTIVE: Polycystic ovary syndrome (PCOS) is a common reproductive disorder characterised by insulin resistance and often associated with hirsutism. Insulin sensitising agents, such as metformin, improve both the biochemical and reproductive parameters; however, no study has been designed to specifically assess the effect of metformin on hair growth. DESIGN AND PATIENTS: Sixteen women with PCOS and hirsutism were enrolled into a 14 month (two 6 month phases with a 2 month washout) double-blind placebo-controlled cross over study. MEASUREMENTS: Hirsutism was assessed using the Ferriman and Gallwey (F-G) score, patient self-assessment and growth velocity. Weight, height and waist-hip ratio were recorded. Gonadotrophins, androgens, plasma glucose and lipids were also measured. RESULTS: Ten women completed the full 14 month study. There was a significant improvement in hirsutism at the end of the metformin phase compared with placebo: F-G score 15.8+/-1.4 vs 17.5+/-1.2 (P=0.025) and patient self-assessment 2.4+/-0.1 vs 3.3+/-0.3 (P=0.014). Growth velocity, in millimetres per day at the end of each phase also improved (0.67+/-0.17 vs 0.77+/-0.11; P=0.03). There was a non-significant improvement in both sex hormone binding globulin (SHBG) and free androgen index (FAI), although there was a significant difference between baseline and metformin treatment for SHBG (P=0.023) and FAI (P=0.036). Metformin treatment also reduced weight significantly (91.5+/-7.6 vs 94.0+/-9.8 kg; P=0.009) and led to a significant improvement in cycle frequency (0.53+/-0.12 vs 0.35+/-0.08 cycles per month; P=0.008). CONCLUSION: We have demonstrated that metformin treatment in a group of women with PCOS results in a clinically and statistically significant improvement in hair growth compared with placebo.     

多囊卵巢综合征的诊治进展

多囊卵巢综合征(PCOS)病因不明,与胰岛素抵抗和高胰岛素血症密切相关。因不同人群临床表现存在高度异质性,故PCOS诊断标准尚存在争议,因而PCOS生物标志物成为研究热点。PCOS治疗包括调节生活方式,改善代谢紊乱、高雄激素血症以及生殖异常。本文综述了PCOS发病特点、诊断标准及治疗方式的最新进展。