Changes in anti-Müllerian hormone serum concentrations over time suggest delayed ovarian ageing in normogonadotrophic anovulatory infertility

BACKGROUND: Anti-Müllerian hormone (AMH), produced by growing pre-antral and early antral ovarian follicles, has been shown to be a useful marker for ovarian ageing. Serum AMH concentrations are elevated during reproductive life in anovulatory women, especially in those patients exhibiting polycystic ovaries (PCO). The current study was designed to investigate whether the decrease in AMH serum concentrations over time is different comparing women with normogonadotrophic anovulation [World Health Organization (WHO) group 2 (including polycystic ovary syndrome (PCOS)] and normo-ovulatory controls. METHODS AND RESULTS: AMH serum levels were assessed on two occasions in 98 patients suffering from WHO 2 anovulatory infertility as well as in 41 normo-ovulatory premenopausal women. Median time interval between both visits was 2.6 years (range 0.3-9.0) for WHO 2 patients compared with 1.6 years (range 1.0-7.3) in controls. Serum AMH concentrations were significantly (P < 0.0001) elevated on both occasions in WHO 2 patients (AMH1, median = 7.5 microg/l, range 0.1-35.8; and AMH2, median = 6.7 microg/l, range 0.0-30.6) compared with controls (AMH1, median = 2.1 microg/l, range 0.1-7.4; and AMH2, median = 1.3 microg/l, range 0.0-5.0). Regression analysis, corrected for age, indicated a significant relative decrease in serum AMH concentrations over time for both groups (P < 0.001). However, the decline in serum AMH in WHO 2 patients was significantly less compared with controls (P = 0.03). CONCLUSION: The present longitudinal study shows that serum AMH concentrations decrease over time both in women presenting with WHO 2 anovulatory infertility and in normo-ovulatory controls. The decrease in WHO 2 patients is less pronounced despite distinctly elevated concentrations. This observation may suggest retarded ovarian ageing and hence a sustained reproductive life span in these patients.     

Does the addition of recombinant LH in WHO group II anovulatory women over-responding to FSH treatment reduce the number of developing follicles? A dose-finding study

BACKGROUND: In anovulatory women undergoing ovulation induction, addition of recombinant human LH (rLH) to FSH treatment may promote the dominance of a leading follicle when administered in the late follicular phase. The objective of this study was to find the optimal dose of rLH that can maintain the growth of a dominant follicle, whilst causing atresia of secondary follicles. METHODS: Women with infertility due to anovulation and over-responding to FSH treatment were randomized to receive, in addition to 37.5 IU recombinant human FSH (rFSH), either placebo or different doses of rLH (6.8, 13.6, 30 or 60 microg) daily for a maximum of 7 days. The primary efficacy endpoint was the proportion of patients who had exactly one follicle > or = 16 mm on hCG day. RESULTS: Among 153 enrolled patients, the five treatment groups were similar in terms of baseline characteristics. The proportion of patients with exactly one follicle > or = 16 mm ranged from 13.3% in the placebo group to 32.1% in the 30 microg rLH group (P = 0.048). The pregnancy rate ranged from 10.3% in the 60 microg group to 28.6% in the 30 microg rLH group. Adverse events were similar between groups. CONCLUSIONS: In patients over-responding to FSH during ovulation induction, doses of up to 30 microg rLH/day appear to increase the proportion of patients developing a single dominant follicle (> or = 16 mm). Our data support the 'LH ceiling' concept whereby addition of rLH is able to control development of the follicular cohort.     

Human follicle-stimulating hormone produced by recombinant DNA technology: a review for clinicians

Human follicle-stimulating hormone (FSH) is now produced in vitro by recombinant DNA technology. FSH being a complex heterodimeric protein, a eukaryotic cell line has been selected for expression work (Chinese hamster ovary cells). The pharmaceutical preparation of recombinant human FSH (r-FSH) differs from that of human menopausal gonadotrophin (HMG) and the first generation of urinary human FSH (u-FSH) in terms of (i) source of bulk materials, (ii) purity and specific activity, (iii) batch to batch consistency, and (iv) complete absence of luteinizing hormone (LH) activity. Pharmacokinetic characterization of r-FSH has shown an absolute bioavailability of approximately 75% after both s.c. and i.m. administration and an apparent terminal half-life of 37 +/- 25 h. These characteristics are very similar to those of u-FSH. Clinical efficacy and safety are currently demonstrated through several randomized, well controlled studies, comparing r-FSH administered s.c. with u-FSH administered i.m. for stimulating follicular development prior to assisted reproduction treatment and in World Health Organization (WHO) group II anovulation. To date, approximately 1000 patients have been treated with r-FSH. Moreover, r-FSH has recently been used successfully in association with recombinant human LH for inducing ovulation and pregnancy in WHO group I anovulatory patients. At this stage of r-FSH preparation assessment, it is likely that r-FSH will replace all urinary-derived FSH preparations for stimulating ovarian follicular development. For clinicians, current experience with r-FSH indicates that it should be used with the regimes and doses applied to u-FSH.     

Impaired vascular function in exercising anovulatory premenopausal women is associated with low bone mineral density

In estrogen‐deficient post‐menopausal women, osteoporosis shares a common link with cardiovascular disease risk, including endothelial dysfunction. The current study sought to examine associations between bone mineral density (BMD) and endothelial function in estrogen‐deficient premenopausal women with exercise‐associated menstrual disturbances. Recreationally trained women (24.3 ± 0.8 years; overall mean ± SEM) who were estrogen deficient (amenorrheic or eumenorrheic anovulatory cycles; E2Def; n = 13) or estrogen replete (eumenorrheic ovulatory cycles; E2Rep; n = 14) were studied. Total body and lumbar BMD (L1‐L4) were determined using dual‐energy X‐ray absorptiometry. Serum markers of oxidative stress (oxidized low‐density lipoprotein; OxLDL), energy deficiency (triiodothyronine), and bone turnover (osteocalcin, c‐telopeptide X, P1NP) were assessed. Estrogen exposure was determined by assessing daily urinary estrone‐3‐glucuronide (E1G) across a monitoring period. Calf blood flow (CBF), an index of endothelial function, was measured using strain‐gauge plethysmography. CBF, total body and L1‐L4 BMD, triiodothyronine and E1G were lower (P < 0.05), and c‐telopeptide crosslinks higher (P < 0.05) in E2Def. Osteocalcin and OxLDL did not differ (P > 0.05) between groups. L1‐L4 BMD, osteocalcin, and E1G were the strongest predictors of CBF (R²=0.615, P < 0.001). CBF was the strongest predictor of L1‐L4 BMD (R²=0.478, P < 0.001). L1‐L4 (r = 0.558, P = 0.008) and CBF (r = 0.534, P = 0.004) were independently correlated with E1G. In young recreationally trained premenopausal women with anovulatory menstrual disturbances, low CBF predicts decreased lumbar BMD, suggesting impaired peripheral endothelial function may predict early unfavorable changes in bone metabolism. This finding may be of relevance in the early detection of cardiovascular and bone health decrements in otherwise healthy estrogen‐deficient premenopausal women.     

The excess in 2-5 mm follicles seen at ovarian ultrasonography is tightly associated to the follicular arrest of the polycystic ovary syndrome

BACKGROUND: We previously hypothesized that the excess of 2–5 mmfollicles seen at ovarian ultrasonography might be involvedin the follicular arrest (FA) of polycystic ovary syndrome (PCOS),independently from the main putative contributors of FA, namelyhyperandrogenism and hyperinsulinism. METHODS: A multivariate statistical analysis was applied retrospectivelyto clinical, biological and ultrasound data that were consecutivelycollected during 5 years in 457 patients with polycystic ovariesand in 188 age-matched non-hyperandrogenic and regularly cyclingcontrols without PCO at ultrasound. RESULTS: Stepwise discriminant analysis indicated that in PCOS the 2–5 mmfollicle number (FN) gave the strongest correlation to severityof the FA, followed by age and then by fasting insulin level.The other variables [waist circumference (WC), 6–9 mmFN, serum testosterone, FSH, LH and ovarian area] were rejectedby the analysis. Multiple linear regression indicated a significantand independent negative relationship between the 2–5and 6–9 mm FN in the PCOS (r = – 0.186, P <0.01) and control groups (r = – 0.281, P < 0.01). InPCOS only, the 6–9 mm FN was negatively and independentlyrelated to the WC (r = – 0.108, P < 0.05). CONCLUSIONS: The size of the 2–5 mm follicle pool is an independentand important contributor to the FA of PCOS. This result couldbe explained by an exaggerated physiological inhibitory effectfrom this pool on the terminal follicle growth. The metabolicderangement of PCOS that also contributes to the FA would actthrough a different mechanism.     

低促性腺激素性腺功能减退症患者的促排卵

低促性腺激素性腺功能减退症(hypogonadotropic hypogonadism,HH)是一种罕见的、以低促性腺激素为特征的、引起第二性征及生殖系统发育障碍的疾病。本文将对该疾病定义、病因、临床表现、诊断及治疗进行全面的介绍。由于HH主要影响育龄女性的生育力,因此诱发排卵以及恢复生育力是该疾病治疗中的关键。治疗HH促排卵的方法较正常人特殊而且复杂,本文将着重介绍HH促排卵的各种原理和方法,同时结合最新的国内外进展以及临床实践经验对各种方法的有效性进行探讨。     

口服妈富隆并延长氯米芬用药时间治疗耐氯米芬的无排卵患者

目的评价常规服用氯米芬促排卵失败的妇女口服避孕药妈富隆配合延长氯米芬服用时间促排卵的治疗效果。方法114例患者在采用传统方法促排卵连续3个周期失败后,改服妈富隆2个周期以上。自停药后月经第5天开始服用氯米芬(50mg/d)促排卵,阴道B超(TVS)监测记录卵泡生长,至出现优势卵泡停服。B超监测排卵经过以及子宫内膜厚度的变化。结果114例患者在服用氯米芬5天后有37例出现优势卵泡,35例成功排卵,2例出现卵泡黄素化未破裂综合征(LUFS);延长服药时间后又有34例成功排卵,17例出现LUFS,13例出现卵泡发育,但未形成优势卵泡即闭锁;13例无卵泡发育。结论对于耐氯米芬的无排卵患者口服妈富隆联合延长氯米芬服药时间,是一种有效的促排卵方案。     

The Use of a Combined Regimen of GnRH Agonist Plus a Low-Dose Oral Contraceptive Improves the Spontaneous Pulsatile LH Secretory Characteristics in Patients with Polycycstic Ovary Disease After Discontinuation of Treatment

Purpose: The fertility rate in women with polycystic ovarydisease (PCOD) is influenced by the type of treatmentreceived. The present study evaluated the possiblecorrelation between treatment and pulsatile release ofgonadotropins. Methods: Spontaneous episodic secretion of luteinizinghormone (LH) and follicle-stimulating hormone (FSH) andhormonal parameters were monitored before and after 1, 3, and6 months after treatments suspension. Twenty-four PCODpatients were randomnly divided into two groups of 12subjects. Group A was treated with gonadotropin-releasinghormone (GnRH)-analogue plus oral contraceptive (OC).Group B was treated only with OC. Both groups were treatedfor 6 months and followed up for 6 months. Results: In all subjects the therapeutic regimens reducedthe androgenic milieau and the gonadotropin plasma levels.Spontaneous pulsatile secretion of LH and FSH wassignificantly modified in both groups, but patients who receivedthe combined regimen showed a significantly greaterreduction of LH plasma levels and a significantly greater decreaseof LH pulse amplitude throughout the 6 months aftertreatment suspension. Ferriman=nGallway score and ovarianvolumes were significantly reduced in patients who receivedthe combined treatment than in the OC-treated patients. Conclusions: These data support the evidence of a higherefficacy of the combination of GnRH-a + OC than OC alonein restoring a normal and adequate spontaneous episodicgonadotropin discharge and in decreasingFerriman—Gallway score and ovarian volumes in patients with PCOD.     

氯菧酚胺小量联合应用治疗排卵障碍性不孕症

本文报告采用小剂量clomephene合并绒毛膜促性腺激素,雌激素和皮质激素等药物,治疗排卵障碍性不孕症136例的结果。共有6个病种包括子宫内膜增殖症、月经稀发、多囊卵巢综合征、黄体期缺陷、无排卵月经和继发性闭经。本组病例的排卵率和妊娠率分别为78.68％和59.56％。并结合文献对联合用药的基本内分泌原理进行了复习和讨论。作者认为适当的病例选择,合理的药物配伍和严密的监护措施是治疗成功的关键。