中医综合治疗排卵障碍性不孕症中促排卵效应的临床疗效研究

目的:观察中医综合治疗排卵障碍性不孕症中促排卵效应的临床疗效。方法:95例排卵障碍性不孕症患者随机分成中医综合组、中西医结合组及西医组,中医综合组采用中药人工周期、针灸及耳穴压豆促排卵,中西医结合组用中药人工周期及氯米芬促排卵,西医组用氯米芬促排卵。结果:中医综合组33例中,排卵29例,占87.88%,妊娠25例,占75.76%;中西医结合组30例中,排卵24例,占80.00%,妊娠15例,占50.00%;西医组32例中,排卵18例,占56.25%,妊娠8例,占25.00%;3组比较妊娠率有显著差异(P0.05);中医综合组、中西医结合组与西医组比较排卵率有显著差异(P0.05)。结论:中医综合治疗促排卵疗效好,可明显提高受孕率。     

吡格列酮联合他莫昔芬治疗多囊卵巢综合征的疗效观察

目的探讨盐酸吡格列酮片联合枸橼酸他莫昔芬片治疗多囊卵巢综合征的临床疗效。方法选取2014年9月—2017年10月江油市人民医院妇科收治的多囊卵巢综合征患者100例为研究对象,将所有患者随机分为对照组和治疗组,每组各50例。对照组患者于月经周期开始的第5天口服枸橼酸他莫昔芬片,20 mg/次,1次/d。治疗组患者在对照组治疗的基础上早餐后口服盐酸吡格列酮片,30 mg/次,1次/d。以21 d为1个疗程,两组患者均连续治疗3个疗程。比较两组治疗前后排卵情况、临床症状、卵巢情况、性激素水平、胰岛素抵抗指标和不良反应发生情况。结果治疗后,对照组患者成熟卵泡数为(1.6±0.5)个,排卵率为64.0%;治疗组患者成熟卵泡数为(2.2±0.5)个,排卵率为88.0%,两组排卵情况比较差异有统计学意义(P0.05)。治疗后,两组月经稀发、痤疮、多毛例数均显著降低,同组治疗前后比较差异有统计学意义(P0.05);且治疗后治疗组临床症状例数均显著少于对照组,两组比较差异具有统计学意义(P0.05)。治疗后,两组卵巢体积显著降低,子宫内膜厚度显著增加,同组治疗前后比较差异有统计学意义(P0.05);且治疗后治疗组卵巢情况显著优于对照组,两组比较差异具有统计学意义(P0.05)。治疗后,两组黄体生成素(LH)、睾酮(T)水平明显降低,促卵泡激素(FSH)、雌二醇(E2)水平明显升高,同组治疗前后比较差异有统计学意义(P0.05);且治疗后治疗组性激素水平改善显著优于对照组,两组比较差异具有统计学意义(P0.05)。治疗后,两组空腹血糖(FPG)、空腹胰岛素(FINS)、胰岛素抵抗指数(HOMA-IR)均显著降低,同组治疗前后比较差异有统计学意义(P0.05);且治疗后治疗组胰岛素抵抗指标显著低于对照组,两组比较差异具有统计学意义(P0.05)。治疗后,治疗组不良反应发生率为6.0%,明显低于对照组的16.0%,两组比较差异具有统计学意义(P0.05)结论盐酸吡格列酮片联合枸橼酸他莫昔芬片治疗多囊卵巢综合征疗效显著,可显著改善患者的临床症状,促进性激素紊乱和胰岛素抵抗情况的恢复,具有一定的临床推广应用价值。     

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。     

有生育要求的多囊卵巢综合征患者的治疗

多囊卵巢综合征(polycystic ovary syndrome,PCOS)是无排卵性不孕常见的原因,有多种非药物性和药物性方法帮助有生育要求的PCOS患者排卵并怀孕。一线疗法包括改变生活方式和克罗米芬治疗。对于克罗米芬抵抗的PCOS患者可采用二线疗法:使用促性腺激素(Gonadotrophin,Gn)、腹腔镜下卵巢打孔术(laparoscopic ovarian drilling,LOD)或者胰岛素增敏剂。如果治疗无效或合并其他不孕因素,可采用三线疗法——辅助生殖技术(assisted reproductive technology,ART)。本文重点介绍每种疗法的特点和治疗进展,以便为PCOS患者制定更加个性化的治疗方案提供参考。     

In vivo imaging reveals an essential role of vasoconstriction in rupture of the ovarian follicle at ovulation

Rupture of the ovarian follicle releases the oocyte at ovulation, a timed event that is critical for fertilization. It is not understood how the protease activity required for rupture is directed with precise timing and localization to the outer surface, or apex, of the follicle. We hypothesized that vasoconstriction at the apex is essential for rupture. The diameter and blood flow of individual vessels and the thickness of the apical follicle wall were examined over time to expected ovulation using intravital multiphoton microscopy. Vasoconstriction of apical vessels occurred within hours preceding follicle rupture in wild-type mice, but vasoconstriction and rupture were absent in Amhr2^cre/+SmoM2 mice in which follicle vessels lack the normal association with vascular smooth muscle. Vasoconstriction is not simply a response to reduced thickness of the follicle wall; vasoconstriction persisted in wild-type mice when thinning of the follicle wall was prevented by infusion of protease inhibitors into the ovarian bursa. Ovulation was inhibited by preventing the periovulatory rise in the expression of the vasoconstrictor endothelin 2 by follicle cells of wild-type mice. In these mice, infusion of vasoconstrictors (either endothelin 2 or angiotensin 2) into the bursa restored the vasoconstriction of apical vessels and ovulation. Additionally, infusion of endothelin receptor antagonists into the bursa of wild-type mice prevented vasoconstriction and follicle rupture. Processing tissue to allow imaging at increased depth through the follicle and transabdominal ultrasonography in vivo showed that decreased blood flow is restricted to the apex. These results demonstrate that vasoconstriction at the apex of the follicle is essential for ovulation.During ovulation in typically mono-ovulatory species such as humans, as well as in poly-ovulatory species such as rodents, the oocyte is released from the preovulatory follicle by extrusion through a rupture site on the outer surface, or apex, of the follicle, which protrudes from the surface of the ovary (1). Precise timing and accurate spatial localization of rupture at the apex are essential to allow capture of the oocyte by a hormonally primed oviduct where fertilization occurs, but the mechanisms involved are not yet understood. The rupture site breaches multiple layers of cells and their associated extracellular matrix and basement membranes (2). These include the single layer of epithelial cells that covers the surface of the ovary, the basement membrane that supports it, and the multiple cell layers comprising the wall of the preovulatory follicle. The outer wall of the ovarian follicle contains androgen-secreting theca cells and extensive vasculature. This vasculature consists of an inner and an outer plexus of capillaries with associated arterioles and venules that supply nutrients to the entire follicle (3–5). Underlying the theca and separated from it by a basement membrane is the avascular granulosa cell layer that serves as the major source of estrogen. The oocyte resides in the center of the follicle surrounded by multiple layers of specialized granulosa cells known as “cumulus cells.” In a mature preovulatory follicle, formation of a fluid-filled antral cavity separates the oocyte–cumulus complex from the mural granulosa cells that form the wall of the follicle except at a region known as the “stalk,” which connects the oocyte–cumulus complex to the antral granulosa cells of the follicle wall. At ovulation the oocyte is released from the follicle in association with attached cumulus cells.The preovulatory release of surge levels of luteinizing hormone (LH) from the anterior pituitary acts on receptors in the follicle to trigger events critical for the rupture and remodeling of the follicle and differentiation of granulosa and theca cells into progesterone-producing cells of the corpus luteum. The cumulus cells are induced to secrete a mucoelastic extracellular matrix which causes loosening of contacts between granulosa cells and between granulosa cells and the oocyte, a process known as “cumulus expansion,” which is essential for ovulation (1). Expression of proteases belonging to several major families, including the matrix metalloproteinase, plasminogen activator/plasmin, and ADAMTS (a disintegrin and metalloproteinase with thrombospondin-like motifs) families, increases. Simultaneously, follicle cells express protease inhibitors such as tissue inhibitors of metalloproteinases (TIMPs 1–4) and plasminogen activator inhibitors (PAI 1–3) (6, 7). The increase in protease activity is essential for rupture of the follicle and for the breakdown of the basement membrane separating theca and granulosa cells to allow the ingrowth of blood vessels to establish the corpus luteum. The mechanisms that regulate the balance of protease and protease inhibitor activity in the follicle to allow precise rupture at the apex while protecting most of the follicle structure from protease activity are not understood (1, 6, 7).We postulated that vasoconstriction of vessels within the theca at the apex of the follicle is required to promote follicle rupture. Our first approach was to examine mice with conditional expression of a dominant active allele of smoothened (SMO), the transmembrane protein that relays signaling by the hedgehog (HH) pathway. In these Amhr2^cre/+SmoM2 mice, preovulatory follicles develop normally in many respects, including changes in the expression of critical genes in response to the preovulatory LH surge (8, 9). However, follicles fail to rupture, and oocytes remain trapped as the follicles luteinize. The major ovarian phenotype in these mice is a pronounced deficiency of vascular smooth muscle (VSM) surrounding vessels in the theca cell layer, whereas other vessels that are present throughout the stroma of the ovary have normal maturation with VSM. Because VSM is required for vasoconstriction, the mice provided a model to test whether failure of vasoconstriction contributes to anovulation. In additional experiments with wild-type mice, we blocked the increase in the expression of endothelin 2 (Edn2) by granulosa cells that normally occurs within hours before follicle rupture (10, 11). Because EDN2 is a potent vasoconstrictor, this approach allowed us to test the effect on follicle rupture of inhibiting vasoconstriction versus treatment with exogenous compounds to restore vasoconstriction. In addition, treatment of wild-type mice with EDN2 receptor antagonists was used to test the role of EDN2 in vasoconstriction and rupture. Vasoconstriction and changes in the follicle wall were monitored repeatedly relative to the time of ovulation using intravital multiphoton microscopy.     

Effect of oral administration of a continuous 18 day regimen of meloxicam on ovulation: experience of a randomized controlled trial

Background

Cyclooxygenase-2 (COX-2) is expressed in all female reproductive organs. Therefore, inhibitors of COX-2 may affect reproductive function. We evaluated the effect of extended administration of meloxicam on ovulation and the menstrual cycle. Our hypothesis was that meloxicam administered from menstrual cycle day 5- 22 could interfere with follicular rupture, without disrupting the menstrual cycle, and could be a potential non-hormonal contraceptive method.

Methods

The study was conducted in 56 healthy sterilized women. Before the onset of treatment and after the end of treatment, participants were observed during a control cycle to ensure that they had progesterone (P₄) serum levels (> 12 nmol/l) consistent with ovulation. Participants were treated for 18 days, during three consecutive cycles. They were randomized to 15 or 30 mg/day. The menstrual cycle was monitored with serial ultrasound and hormone assays in blood.

Results

Fifty-six volunteers completed the study. In 55% of cycles treated with 15 mg/day and in 78% of cycles treated with 30mg/day (p<0.001) we observed dysfunctional ovulation defined as follicular rupture not preceded 24–48 h earlier by an LH peak or preceded by a blunted LH peak (< 21 IU/l) or not followed by an elevated serum P₄ level > 12 nmol/l. Ovulation was observed in 44.6% and in 21.7% of women in the lower dose group and the higher dose group, respectively. There were no differences between the two doses in other parameters measured. There were no serious adverse events and adverse events were not different between doses or between control and treated cycles.

Conclusions

Although administration of meloxicam on menstrual cycle days 5- 22 resulted in a dose-dependent inhibition of ovulation, more than 20% of subjects had normal ovulation with the highest dose.

Implications

Previous studies have shown that oral meloxicam can delay follicle rupture. This study investigated daily oral meloxicam as a non-hormonal contraceptive. Since ovulation occurs in over 20% of cycles even with a high dose of 30 mg daily, it is not likely that the approach would be a highly effective contraceptive strategy.     

Pregnancy outcomes following pulsatile GnRH treatment: results of a large multicenter retrospective study

Objectives

The aim of the present study was to evaluate the efficacy of pulsatile GnRH treatment in a large French cohort of patients with hypogonadotropic hypogonadism.

Methods

A retrospective study involving all women treated with pulsatile GnRH, over a 3-year period, in 24 French centers. Pregnancy rate and pregnancy outcome were the criteria for evaluation.

Results

The study included 248 women who received a total of 829 treatment cycles. The treatment routes of administration were subcutaneous (56.1% of the patients), intravenous (31.1%), or both (12.7%). The pregnancy rate per treatment cycle was 25%, while the mean number of cycles needed to obtain a pregnancy was 2.8 ± 1.7. The miscarriage rate was 8.2% and the multiple pregnancy rates 8.8%. The mean delivery term was 38.4 ± 2.4 weeks and the mean birth weight was 3009 ± 561 g. No severe ovarian hyperstimulation was recorded. Ovarian cysts occurred in 2.3% of the treatment cycles, local allergies in 1.7%.

Conclusion

Our study has shown that pulsatile GnRH treatment was well tolerated, without severe hyperstimulation. It induced a good pregnancy rate with favorable pregnancy outcomes.