Basic review: endocrinology of the normal menstrual cycle

(1) The normal menstrual cycle depends on hormonal relationships between the hypothalamus, pituitary, and ovary. The mechanisms of hormonal control involve both long-looped feedback control (i.e., E2 feedback to the hypothalamus) and local control (i.e., internal ovary). A hormone may have different effects depending on concentration and timing of appearance during the menstrual cycle. (2) There is a single gonadotropin-releasing hormone that governs both FSH and LH release from the pituitary. FSH and LH release is governed by both the concentration and timing of the hypothalamic-releasing factor, GNRH. (3) The follicular or proliferative phase of the menstrual cycle is characterized by the selective development of a dominant follicle. The follicular phase biochemistry is notable for increasing estradiol production, which inhibits GNRH secretion but increases the gonadotropin pool and prepares the follicle for LH influence by stimulating LH receptors. (4) Ovulation occurs secondary to LH surge triggered by increasing levels of E2 acting in a positive feedback loop on the pituitary. (5) Corpus luteum development is signaled by increasing serum progesterone and is largely an autonomous ovarian phenomenon not subject to a great deal of control by hypothalamic or pituitary hormonal controls, because high levels of progesterone inhibit GNRH and gonadotropins.     

GnRH agonists: gonadorelin, leuprolide and nafarelin.

Gonadotropin-releasing hormone (GnRH), a decapeptide synthesized and released by the hypothalamus, regulates production and release of the gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH) by the adenohypophysis. Parenterally administered GnRH was initially used diagnostically as a test of adenohypophyseal reserve of LH and FSH. Subsequently, native GnRH was used therapeutically to treat hypothalamic hypogonadal and infertility states in both men and women. Because of the low potency and short half-life of native GnRH, long-acting, potent analogs have been developed that suppress secretion of native pituitary gonadotropins, resulting in medical gonadectomy. When administered parenterally and, more recently, intranasally, these compounds are useful in the management of prostate and breast carcinoma, endometriosis and uterine leiomyomata, precocious puberty and nontumorous ovarian hyperandrogenic syndromes.     

G protein-coupled receptors of the hypothalamic-pituitary-gonadal axis: a case for Gnrh, LH, FSH, and GPR54 receptor ligands

The hypothalamic-pituitary-gonadal (HPG) axis, important in reproduction and sex hormone-dependent diseases, is regulated by a number of G protein-coupled receptors. The recently "deorphanized" GPR54 receptor activated by the peptide metastin is thought to be the key regulator of the axis, mainly by releasing gonadotropin-releasing hormone (GnRH) from the hypothalamus. The latter decapeptide, through the activation of the GnRH receptor in the anterior pituitary, causes the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which subsequently activate their respective receptors on the gonadotrope cells. In this review we will discuss the small molecule agonists and antagonists that are currently being developed to intervene with the action of these four receptors. For GnRH receptors, 14 different chemical classes of non-peptidic antagonists have been reported, while for the LH receptor three classes of agonists have been described. Both agonists and antagonists have been introduced for the FSH receptor. Recently, the first non-peptidic agonist for GPR54 was reported.     

Selective inhibition of follicle-stimulating hormone secretion by estradiol. Mechanism for modulation of gonadotropin responses to low dose pulses of gonadotropin-releasing hormone

Prepubertal girls and gonadotropin-releasing hormone (GnRH)-deficient females secrete follicle-stimulating hormone (FSH) preferentially in response to intravenous GnRH. With continued pulsatile GnRH stimulation, FSH secretion is reduced when plasma estradiol (E2) is increasing. To delineate the mechanisms involved in these changing gonadotropin responses, e studied the effect of low dose (0.025 micrograms/kg) pulsatile injections of GnRH in females with varying degrees and/or duration of endogenous GnRH deficiency (idiopathic panhypopituitarism, PHP; isolated growth hormone deficiency, IGHD; isolated gonadotropin deficiency, IGD; and anorexia nervosa, AN; both at low body weight and after weight regain). In patients presumed to have the most severe GnRH deficiency (PHP), responses of both FSH and luteinizing hormone (LH) were small and delayed, and no increase in plasma estradiol occurred during the 5 d of GnRH injections. In patients previously exposed to prepubertal or adult levels of endogenous GnRH secretion (IGHD, IGD, AN at low body weight), a rapid initial FSH response occurred that subsequently declined when plasma estradiol rose to concentrations greater than 40-50 pg/ml. Prior therapy with estrogen (micronized estradiol, Estrace) abolished FSH responses but LH responses were only slightly impaired. The degree of FSH response was dependent upon the time of initiation of estrogen relative to the onset of GnRH injections. Administration of estrogen after the first GnRH injection inhibited gonadotropin responses, whereas later estrogen therapy (after 1 d of GnRH pulses) blunted the GnRH induced FSH secretion without significantly impairing the LH response. In weight-regained anorexic patients who had spontaneous pulsatile LH secretion and a mean basal plasma estradiol concentration of 53 +/- 15 pg/ml, administration of GnRH pulses did not change plasma LH and a minimal FSH response was seen. The data indicate that the pattern of gonadotropin responses to low dose GnRH injections depends upon the degree of previous exposure of the pituitary to endogenous GnRH. Furthermore, estradiol selectively inhibits FSH secretion by a direct action on the pituitary gland. This action of estradiol provides an explanation for the selective reduction in FSH responses to GnRH seen during pubertal maturation in girls and during the mid-follicular stage of the menstrual cycle.     

Effect of porcine follicular fluid on LH and FSH secretion in rats

To investigate a mode and a site of action of inhibin on FSH and LH secretion, in vivo and in vitro effects of porcine follicular fluid (PFF) on FSH and LH secretion were studied in male rats. PFF administered i.v. suppressed basal FSH levels for 1-8 hr, but did not alter LH levels. On the contrary, PFF given either 1 or 6 hr in advance, suppressed LH-RH stimulated LH responses as well as LH-RH induced FSH responses. In cultured pituitary cells PFF exerted a partial suppressive effect on LH release. PFF suppressed LH release only under the maximal stimulation with 10(-10) M LH-RH and 0.1 mM 3-isobutyl-1-metylxanthine (IBMX) to a lesser degree compared with uniform and greater suppression on FSH release regardless of the experimental conditions. Above results showed a selective suppressive effect of PFF on FSH release and synthesis with a less inhibitory effect on LH release mainly at the pituitary level.     

The corpus luteum

The primary function of the corpus luteum is secretion of progesterone for maintenance of pregnancy. The development and function of the corpus luteum from residual follicular granulosa and theca cells after ovulation is induced by the midcyclic peak of LH secretion followed by further pulsatile LH release. Due to this stimulation the follicular granulosa and theca cells are converted to large and small luteinized cells with high proliferation rate. During this process Vascular-Endothelial-Growth Factor (VEGF) plays a major role as a potent stimulator of neo-angiogenesis. Formation of new blood vessels is essential to ensure supply of LDL-Cholesterol as substrate for steroidogenesis. If pregnancy does not occurs, the corpus luteum must regress to initiate another cycle. Luteal regression seems to be initiated by PGF2 alpha which is secreted from the uterus. PGF2 alpha, reduces luteal blood flow and progesterone synthesis. Furthermore it is a potent inducer of apoptosis. If pregnancy occurs, sustained secretion of progesterone and other substances like estradiol and relaxin are required to provide an appropriate uterine environment for maintenance of pregnancy. In that case the corpus luteum is further stimulated by hCG secreted by the blastocyst and the trophoblast-cells until 8/9 weeks of gestational age, when synthesis and secretion of steroids is taken over by the placenta.     

彩色多普勒超声检查与激素放免测定监测排卵的临床应用

应用Acuson-128彩色多普勒超声仪采用经腹法对26例妇女按月经周期的不同时间观察了卵泡发育及排卵前后的卵巢内血流显像及频谱变化,同时进行FSH、LH、P及雌二醇的放免测定。结果是,排卵前卵巢内动脉供血不丰富。频谱为低振幅高阻抗型;LH值呈上升趋势;排卵期75％出现舒张期血流;排卵后功能侧卵巢血流速度增高,频谱为高振幅低阻抗型,舒张期血流逐渐减慢或消失,孕酮值达到最高水平。因此彩色多普勒在卵巢内是否出现丰富舒张期供血,是判断功能性卵巢及排卵的可靠依据。     

Gonadotropin in follicular phase in women with luteal phase defect.

Serum FSH and LH in women with luteal phase defect were measured. Their serum FSH and LH were lower than those in normal women and higher than those in women with amenorrhea. Administration of clomiphene citrate to the women with luteal phase defect were effective in 2/3 of the cases. These results are consistent with the hypothesis that a relative deficiency of FSH during the follicular phase results in diminished follicular development and subsequent inadequate corpus luteum maintenance.     

Direct evidence of estrogen modulation of pituitary sensitivity to luteinizing hormone-releasing factor during the menstrual cycle.

To delineate the role of estradiol in the augmented pituitary gonadotropin responsiveness to synthetic luteinizing hormone releasing factor (LRF) seen during high-estrogen phases of the ovulatory cycles (late follicular and midluteal phases), the anti-estrogenic effect of clomiphene citrate (Clomid) on pituitary response to LRF was evaluated during different phases of the ovulatory cycle. Clomid administration (100 mg/day times 5 days) completely negates the augmented gonadotropin responses to LRF (150 mug) during late follicular and midluteal phases observed during the control studies. Thus, a quantitatively and qualitatively similar pituitary sensitivity to LRF during three distinct phases of the menstrual cycle was induced by Clomid treatment that resembles the LRF responsiveness of themale pituitary. The present study demonstrates the pituitary component of the estrogen-induced changes in the sensitivity to LRF. From this and previous data, we conclude that the increases of estradiol secretion associated with the follicular maturation and corpus luteum formation represent a major component of the feedback signal in the modulation of cyclic gonadotropin release occasioned in a large measure by the augmented pituitary sensitivity to LRF.     

Pituitary self-priming actions of gonadotropin-releasing hormone. Kinetics of estradiol''s potentiating effects on gonadotropin-releasing hormone-facilitated luteinizing hormone and follicle-stimulating hormone release in healthy postmenopausal women.

We examined the kinetically distinct characteristics of estradiol's effects upon pituitary luteinizing hormone (LH) and follicle-stimulating hormone (FSH) release in response to pulses of exogenous gonadotropin-releasing hormone (GnRH) in healthy postmenopausal individuals. The putative self-priming actions of GnRH on LH and FSH release were tested by intravenous injections of equal paired doses of GnRH (10 micrograms) before and after 1, 5, 10, and 30 d of pure estradiol-17 beta delivery via an intravaginal silastic ring. Self-priming actions of GnRH, as defined by heightened gonadotropin release in response to the second pulse of GnRH compared with the first, were completely absent in the hypoestrogenemic state. However, estradiol administration unmasked GnRH self-priming in a time-dependent fashion, with maximal expression after 5 and 10 d of steroid replacement, followed by attenuation by 30 d. Since estradiol's modulation of GnRH action was expressed differentially on LH and FSH release, we suggest that such facilitation of GnRH-stimulated pituitary LH and FSH release may provide an additional mechanism for dissociated secretion of gonadotropic hormones in health or disease.     

Ovarian membrane receptors for LH, FSH and prolactin during the menstrual cycle and in polycystic ovary syndrome

To investigate the role of ovarian membrane receptors for LH, FSH and prolactin of patients with developing polycystic ovary (PCO) syndrome, seven patients were selected and the receptor function was studied in relation to changes of several serum hormone levels. The results were compared with those from individuals with regular menstrual cycles in the late follicular (LF; n = 6) and midluteal (ML; n = 6) phases. LH receptor binding in the normal cycle remained low (1.73 +/- 0.14 fmole/mg homogenate protein) in the LF phase and elevated 3 fold in the ML phase. LH receptors in the PCO patients maintained a higher binding level than that in the LF phase, being close to the ML level. FSH receptors were at a high level in the LF phase (4.09 +/- 0.40 fmole/mg homogenate protein), but decreased by 23% in the ML phase. In the PCO group the ovarian FSH receptor showed a high level, near to that in the LF phase. Prolactin receptors showed no significant changes among the two controls and PCO group. PCO patients showed increased levels of serum LH and testosterone and a raised ratio of estrone to estradiol, although there was no change in the serum FSH level. These data suggested that the LH receptor binding in PCO was not so low as to the LF level. A lack of the down-regulation mechanism of LH receptors, in spite of the high level of serum LH in PCO, might be one of the clues to elucidate the pathophysiological mechanism in developing PCO syndrome. Elevated levels of the gonadotropin receptors, especially FSH receptors, seem to be involved in the high incidence of ovarian hyperstimulation during hormone treatment.     

B超引导下经阴道卵泡穿刺治疗耐药PCOS效果

目的 观察B超引导下经阴道卵泡穿刺治疗耐药多囊卵巢综合征（PCOS）并不孕症病人的临床效果,探讨其可行性。方法 选择30例难治性PCOS病人,在B超引导下行经阴道卵巢穿刺术。记录病人手术前后基础激素水平,术后监测排卵,若2个月无排卵,则使用促排卵药物,同时指导性生活,并随访1年,了解妊娠情况。结果 手术后内分泌激素水平改善,手术前后血清黄体生成素（LH）、睾酮（A）、雄烯二酮（T）水平及LH／FSH差异有显著性（t=12．17～35．25,P〈0．01）。治疗后取得较高的排卵率（73．3％）、妊娠率（50．0％）。结论 B超引导下经阴道卵泡穿刺术为耐药PCOS病人的治疗开创了一种简便易行的新途径。     

Transvaginal ultrasonography in the diagnosis and treatment of infertility

The use of transvaginal sonography (TVS) in the management of infertility is gaining increasing popularity. The improved resolution and better tissue textural differentiation afforded by TVS makes this technique useful in monitoring ovarian follicular growth, ovulation, and corpus luteum formation, and in evaluating the normal anatomy of the uterus and the cervix and their cyclic response to ovarian steroids. Adnexal and cul-de-sac abnormalities related to infertility can also be identified. TVS-guided procedures can be accurately and safely performed; transvaginal follicular aspiration, gamete or embryo transfer to the Fallopian tube, and fetal reduction are just a few of the procedures recently introduced to reproductive medicine.     

Regulation of pituitary gonadotropin-releasing hormone receptors by pulsatile gonadotropin-releasing hormone injections in male rats. Modulation by testosterone.

The pattern of the gonadotropin-releasing hormone (GnRH) stimulus is critically important in the regulation of pituitary gonadotropin secretion and continuous infusions down-regulate secretion while intermittent pulses maintain luteinizing hormone (LH) and follicle-stimulating hormone (FSH) responsiveness. We examined the effects of pulsatile GnRH administration on pituitary GnRH receptors (GnRH-R) and gonadotropin secretion in the presence of physiological concentrations of testosterone (T) to elucidate the mechanisms and sites of action of GnRH and T on the pituitary gonadotroph. Castrate male rats received one, two, or four testosterone (T) implants (serum T concentrations of 1.1, 2.4, and 5.2 ng/ml, respectively) to suppress endogenous GnRH secretion. Subsequently, intracarotid pulse injections of GnRH (5-250 ng/pulse) or saline in controls were given every 30 min for 48 h, after which gonadotropin responses and pituitary GnRH-R were measured. In control rats, the T implants prevented the rise in GnRH-R that was seen in castrates (empty implant--600 fmol/mg protein) and maintained receptors at the level that was present in intact animals (300 fmol/mg). Pulsatile GnRH administration increased GnRH-R in castrate T-implanted rats, but the response was dependent on the serum T concentration. With one T implant, increasing GnRH doses per pulse stimulated GnRH-R in a linear manner and the maximum receptor concentration (703 +/- 99 fmol/mg) was seen after the 250 ng GnRH dose. In the presence of two T implants, GnRH-R was maximal (705 +/- 45 fmol/mg) after the 25-ng dose and higher doses did not increase receptors above control values. With four T implants, GnRH doses of 5 ng induced a maximum response, 17-50 ng/pulse did not increase GnRH-R, but receptors were again increased by the 250-ng dose (633 +/- 86 fmol/mg). After 48 h of pulsatile GnRH administration there was no correlation between the number of GnRH-R and LH responses to GnRH. In rats with one or two T implants, LH responses were absent after all but the 250-ng doses. In contrast, LH responsiveness was not impaired in the presence of four implants. Thus, low dose GnRH pulses down-regulate LH secretion by an action at a post GnRH-R site, and this effect is regulated by testosterone. The results show that GnRH, given in a pulsatile manner, regulates its own receptor, and physiological increases in serum T produce a 50-fold increase in the sensitivity of GnRH-R stimulation by GnRH.     

Kisspeptins 对下丘脑-垂体-性腺轴作用机制新进展

近年来,Kisspeptins 的发现使人们对调控青春期和生殖的神经内分泌轴有了新的认识。Kisspeptins 不仅是促进 GnRH 分泌的上游因子,而且调控下丘脑-垂体-卵巢轴,主要表现在促性腺激素分泌的调节、青春期的启动以及生殖功能的调控等方面。 通过对健康人群及生殖内分泌紊乱患者的观察,发现 Kisspeptins 可以刺激 GnRH 分泌,后者诱导 LH 分泌,而且增强 LH 的脉冲频率。这些研究表明 Kisspeptins 将成为生殖内分泌研究的热点,并为生殖内分泌疾病提供新的治疗策略。目前许多动物试验研究证明 Kisspeptins 在以下几个方面也存在潜在的作用,如卵巢的功能的调节、胚胎植入及胎盘的形成。本文将集中收集关于 Kisspeptins 调控 GnRH 的脉冲式分泌的现有的依据,特别是青春期启动及生殖内分泌方面。     

Relative roles of follicle-stimulating hormone and luteinizing hormone in the control of inhibin secretion in normal men.

The glycoprotein hormone inhibin is produced by the Sertoli cells of the testis under the influence of follicle-stimulating hormone (FSH) and is postulated in turn to inhibit FSH secretion. Luteinizing hormone (LH) is not recognized to have an important role in the control of inhibin secretion in any species. To determine the relative roles of FSH and LH in the control of inhibin secretion in man, we examined the effects of selective FSH and LH replacement on serum inhibin levels in normal men whose endogenous gonadotropins were suppressed by testosterone (T). After a 3-mo control period, nine men received 200 mg T enanthate i.m. weekly for 3-9 mo. During T treatment, serum LH and FSH levels were markedly suppressed and serum inhibin levels fell to 40% of control values. While continuing T, 3-5 mo of treatment with purified hFSH (n = 4) or hLH (n = 4) increased the respective serum gonadotropin level into the upper normal range and significantly increased inhibin levels back to 64 and 55% of control values, respectively. Supraphysiological LH replacement with high doses of human chorionic gonadotropin (n = 3) returned serum inhibin levels to 63% of control values. In no case did inhibin levels return fully to control levels. In conclusion, serum inhibin levels fell during gonadotropin suppression and were partially and approximately equally restored by either FSH or LH treatment. FSH presumably acts directly on the Sertoli cell to increase inhibin secretion whereas LH may act via increases in intratesticular T levels and/or other factor(s).     

Establishment of detailed reference values for luteinizing hormone, follicle stimulating hormone, estradiol, and progesterone during different phases of the menstrual cycle on the Abbott ARCHITECT analyzer.

During a normal menstrual cycle, serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol, and progesterone can vary widely between cycles for the same woman, as well as between different woman. Reliable reference values based on the local population are important for correct interpretation of laboratory results. The purpose of our study was to determine detailed reference values for these hormones throughout the menstrual cycle using the Abbott ARCHITECT system. From 20 volunteers (age 20-36 years) with normal cycles and no use of oral contraceptives, samples were taken every day during their cycle. Volunteers received three vaginal ultrasound examinations (days 10 and 13, and 1 or 2 days after ovulation) to measure follicular and corpus luteum development. Hormone levels were measured using the corresponding ARCHITECT assay and were synchronized to the LH peak. Median, and 5th and 95th percentile values were determined for each day of the cycle, as well as for early follicular (days -15 to -6), late follicular (days -5 to -1), LH peak (day 0), early luteal (+1 to +4), mid-luteal (days +5 to +9), and late luteal (days +10 to +14) phases of the cycle. Based on our data, we were able to establish detailed reference values for LH, FSH, estradiol, and progesterone, which should aid in the interpretation of results for these reproductive hormones in a variety of circumstances.     

月经不同时相腹腔镜卵巢囊肿剥离术对卵巢近期功能的影响

目的：探讨月经不同时相腹腔镜卵巢囊肿剥离术对卵巢功能的影响。方法于2010年6月至2013年3月行腹腔镜卵巢囊肿剥离术68例患者,按术时不同月经时相随机分为卵泡组（n=34）和黄体组（n=34）。观察两组手术时间、术中出血量、术前及术后3、6个月时雌二醇（E2）、促卵泡激素（FSH）、促黄体生成素（LH）激素水平、术后患侧卵巢窦卵泡个数以及排卵和月经情况。结果两组手术时间比较差异无统计学意义（P〉0.05）,卵泡组手术出血量较少（P〈0.05）;术后3个月、6个月卵泡组患者血清E2、FSH和LH激素水平较术前无明显变化（P〉0.05）,术后3个月、6个月黄体组血清LH水平与术前比较无明显变化（P〉0.05）,E2水平较术前下降,FSH水平明显升高,差异有统计学意义（P〈0.05）;两组患者术后3个月、6个月窦卵泡数与术前均无明显差异（P〉0.05）;黄体组经期延长、经量过少以及排卵异常发生几率显著高于卵泡组（P〈0.05）。结论腹腔镜下卵巢囊肿剥除术宜选择在卵泡期进行,对卵巢功能影响较小。