Role of pituitary adenylate cyclase‐activating polypeptide in modulating hypothalamic‐pituitary system

Background

Pituitary adenylate cyclase‐activating polypeptide (PACAP) is a multifunctional peptide that is isolated and identified from the ovine hypothalamus, whose effects and mechanisms have been elucidated in numerous studies. The PACAP and its receptor are widely expressed, not only in the hypothalamus but also in peripheral organs.

Methods

The studies on the role of PACAP in the hypothalamic‐pituitary system, including those by the authors, were summarized.

Results

In the pituitary gonadotrophs, PACAP increases the gonadotrophin α‐, luteinizing hormoneβ‐, and follicle‐stimulating hormone β‐subunit expression and the expression of gonadotropin‐releasing hormone (GnRH) receptor and its own receptor, PAC1R. Moreover, a low‐frequency GnRH pulse increases the expression of PACAP and PAC1R more than a high‐frequency GnRH pulse in the gonadotrophs. The PACAP stimulates prolactin synthesis and secretion and increases PAC1R in the lactotrophs. In the hypothalamus, PACAP increases the expression of the GnRH receptors, although it is unable to increase the expression of GnRH in the GnRH‐producing neurons.

Conclusion

The PACAP not only acts directly in each hormone‐producing cell, it possibly might regulate hormone synthesis via the expression of its own receptors or those of other hormones.     

Gamma‐aminobutyric acidA receptor agonist,muscimol, increases KiSS‐1 gene expression in hypothalamic cell models

Purpose

Accumulating evidence indicates that hypothalamic kisspeptin plays a pivotal role in the regulation of the hypothalamic–pituitary–gonadal (HPG) axis. In this study, the direct action of the gamma‐aminobutyric acid (GABA)_A receptor agonist on kisspeptin‐expressing neuronal cells was examined.

Methods

A hypothalamic cell model of rat hypothalamic cell line R8 (rHypoE8) cells and primary cultures of neuronal cells from fetal rat brains were stimulated with a potent and selective GABA_A receptor agonist, muscimol, to determine the expression of the KiSS‐1 gene.

Results

Stimulation of the rHypoE8 cells with muscimol significantly increased the level of KiSS‐1 messenger (m)RNA expression. The ability of muscimol to increase the level of KiSS‐1 mRNA also was observed in the primary cultures of the neuronal cells from the fetal rat brains. The muscimol‐induced increase in KiSS‐1 mRNA expression was completely inhibited in the presence of the GABA_A receptor antagonist. Although muscimol increased the expression of KiSS‐1, the natural compound, GABA, failed to induce the expression of KiSS‐1 in the rHypoE8 cells. Muscimol did not modulate gonadotropin‐releasing hormone expression in either the rHypoE8 cells or the primary cultures of the fetal rat brains.

Conclusions

This study's observations suggest that the activation of the GABA_A receptor modulates the HPG axis by increasing kisspeptin expression in the hypothalamic neurons.     

Clinical outcomes of assisted reproductive technology treatment by using a self‐injection of recombinant human chorionic gonadotropin as the final maturation trigger

Purpose

To evaluate the efficacy and safety of self‐injections of the prefilled recombinant human chorionic gonadotropin (r‐hCG) in a syringe in assisted reproductive technology (ART) treatment for the maturation trigger (MT), as compared to self‐injections of conventional hCG and intranasal administration of gonadotropin‐releasing hormone agonist (GnRH‐a).

Methods

Between January and April, 2017, 396 patients who underwent oocyte retrieval were recruited. Of these, 396 patients were classified into three groups, according to the types of MT: (1) the urinary human chorionic gonadotropin (u‐hCG) group that consisted of patients who had a self‐injection of u‐hCG (n = 127); (2) the GnRH‐a group that received nasal administration of GnRH‐a (n = 159); and (3) the r‐hCG group that had a self‐injection of r‐hCG (n = 110). Several ART outcomes were evaluated.

Results

The mature oocyte retrieval rate was not different between the u‐hCG, r‐hCG, and GnRH‐a groups and the fertilization and cleavage rates were similar between the three groups. The clinical pregnancy rates did not significantly differ between the GnRH‐a group and the u‐hCG group; however, it was significantly lower in the GnRH‐a group, compared to the r‐hCG group. No difference was observed in the incidence of moderate or more severe ovarian hyperstimulation syndrome among the three groups.

Conclusion

The self‐injection of the prefilled r‐hCG is a favorable MT for ART patients.     

Association of follicular fluid volume with membrane stretchability of human metaphase II oocytes following the gonadotropin‐releasing hormone agonist protocol during intracytoplasmic sperm injection

Purpose

The authors previously revealed the association of the follicular fluid (FF) volume with oolemma stretchability following the gonadotropin‐releasing hormone (GnRH) antagonist protocol during intracytoplasmic sperm injection (ICSI). However, the impact of the GnRH agonist protocol on oolemma stretchability remains unclear.

Methods

Data that were obtained from 74 ICSI cycles were reviewed retrospectively. Controlled ovarian stimulation was performed in accordance with the short GnRH agonist protocol. Each follicle was individually aspirated and assigned to one of six groups, according to the FF volume. The oolemma stretchability during ICSI was evaluated by using a mechanical stimulus for oolemma penetration; that is, oolemma penetration with or without aspiration (high vs low stretchability, respectively).

Results

The incidence of low oolemma stretchability was significantly higher in the <1.0 mL group than that in the ≥1.0 mL group. The normal fertilization rate was significantly lower in the <1.0 mL group than that in the 2.0‐<3.0 mL group. The rate of blastocyst development was lower in the <1.0 mL group than that in the 3.0‐<4.0 mL group.

Conclusion

The FF volume potentially was associated with metaphase II oolemma stretchability, fertilization, and blastocyst development.     

Behavior Change Following Implementation of Home‐Based Life‐Saving Skills in Liberia,West Africa

Introduction: Home‐Based Life‐Saving Skills (HBLSS) has been fully integrated into Liberia's long‐term plan to decrease maternal and newborn mortality and morbidity, coordinated through the Ministry of Health and Social Welfare. The objective of this article is to disseminate evaluation data from project monitoring and documentation on translation of knowledge and skills obtained through HBLSS into behavior change at the community level. Methods: One year after completion of HBLSS training, complication audits were conducted with 434 postpartum women in 1 rural county in Liberia. Results: Sixty‐two percent (n = 269) of the women were attended during birth by an HBLSS‐trained traditional midwife or family member, while 38% (n = 165) were attended by a traditional midwife or family member who did not receive HBLSS training. Home‐Based Life‐Saving Skills–trained birth attendants performed significantly more first actions (life‐saving actions taught to be performed after every birth) than the attendants not HBLSS trained. Fourteen percent of our sample (n = 62) reported too much bleeding following the birth. Of these women, approximately half (n = 29) were attended by an HBLSS‐trained traditional midwife or family member. There was a significant difference in secondary actions (those actions taught to be performed when a woman experiences too much bleeding following childbirth) that were reported to have been performed by HBLSS‐trained attendants (mean 5.26, standard deviation [SD] 1.88) and untrained attendants (mean 2.73, SD 1.97; P < .0001). Discussion: Our findings suggest that HBLSS knowledge is being transferred into behavior change and used at the community level by traditional midwives and family members.     

Nicked human chorionic gonadotropin in trophoblastic disease

Abstract. Kohorn EI, Cole L. Nicked human chorionic gonadotropin in trophoblastic disease.
The objectives of this study were to determine: 1) whether high proportions of nicked human chorionic gonadotropin (hCG) in serum at the time of mole evacuation and during postmolar surveillance is indicative of trophoblastic malignancy and 2) to investigate whether measurement of nicked hCG provides clinically more useful information in the management of patients with trophoblastic disease than does measurement of total hCG alone.
"Tumor marker" total hCG, intact hCG, and nicked hCG were measured in serial samples of serum from our serum bank of patients with representative types of trophoblastic disease. "Tumor marker" hCG has been shown to measure all aspects of the hCG molecule. At the time of presentation of all 45 patients, 83.5% of hCG was intact and 16.5% was nicked. These proportions became reversed as hCG declined either spontaneously after hydatidiform mole evacuation or with chemotherapy in patients with postmolar trophoblastic tumor or with metastatic trophoblastic disease.
We conclude that the proportion of nicked hCG compared to intact hCG increases with trophoblastic disease resolution. Measurement of nicked hCG adds no useful clinical information to that provided by reliable measurement of total hCG.     

Self‐Rated “No‐” and “Low‐” Risk Pregnancy: A Comparison of Outcomes for Women in Obstetric‐Led and Midwife‐Led Units in England

ABSTRACT: Background: Debate in the United Kingdom about place of birth often concerns obstetric‐led units and midwife‐led units and relates to notions of risk and safety. Outcomes for these two types of unit are often not comparable because of the restricted selection criteria for midwife‐led units. The purpose of this study was to compare outcomes for women intending to give birth in these different types of unit and whose self‐rated pregnancy risk level was “none” or “low.” Methods: Self‐completion questionnaires were distributed to mothers 8 days after the birth in 9 units (6 midwife led 3 obstetric led) over a 6‐month period. Results: Completed questionnaires were received from 432 women (midwife led = 294, obstetric led = 138). Mothers in midwife‐led units spent shorter times in labor in the unit (p < 0.01), received less analgesia (p < 0.01) and had fewer interventions (p < 0.01), and were more likely to have a normal delivery (p < 0.01) than women in obstetric‐led units. Similar differences were found for both primiparous and multiparous women. In terms of the number of midwives attending each woman, analysis of covariance suggested different models of care depending on type of unit (p < 0.05) and parity (p < 0.01). Conclusions: Since these mothers’ self‐rated risk level was none or low, some comparability of outcomes is permissible. It appears that models of care are significantly different in obstetric‐led units compared with midwife‐led units, leading to greater likelihood of intrapartum intervention, need for analgesia, and assisted or operative delivery. A randomized controlled trial examining such units would permit a conclusive examination of these outcomes. (BIRTH 34:4 December 2007)     

Dexamethasone as an adjuvant therapy for anovulatory,normoandrogenic patients during ovulation induction with exogenous gonadotropins

Objective: The objective of our study was to explore the effect of dexamethasone (DEX), a highly potent, long-acting glucocorticoid, on the treatment outcome of 74 anovulatory women aged 21 to 29 years, with normal gonadotropins, androgen, and prolactin (PRL) serum levels who failed to conceive on antiestrogen therapy. Methods: The patients received human menopausal gonadotropin/human chorionic gonadotropin (hMG/hCG) for ovulation induction. Starting on day 4 of the induced menstruation, hMG was administered in combination with DEX, 0.5 mg at night, or without DEX as an adjuvant treatment. The total amount of gonadotropins used, time required for stimulation, percentage of fertilization, serum estradiol levels, pregnancy rate, cumulative pregnancy rate, and abortions were recorded. Results: There were no differences in either the cumulative pregnancy rate (54.1% in the DEX group and 52.7% in the untreated group) or the abortion rates (21.7% in the DEX group compared to 20.8% in the untreated group). The other parameters investigated also did not differ significantly between the groups. Conclusions: The overall results did not support DEX as a clinically useful adjuvant therapy for anovulatory, normoandrogenic patients.     

Prospective, randomized, crossover study to evaluate the benefit of human chorionic gonadotropin–timed versus urinary luteinizing hormone–timed intrauterine inseminations in clomiphene citrate–stimulated treatment cycles

Objective: To compare two methods of timing IUI, urinary LH monitoring and transvaginal ultrasonography/hCG timing of ovulation, in patients receiving clomiphene citrate.

Design: Prospective, randomized, crossover study.

Setting: Yale University Reproductive Medicine Center.

Patient(s): Infertile couples undergoing IUI because of unexplained infertility, anovulation, or male factor infertility.

Intervention(s): Patients received clomiphene citrate on days 3–7 of the menstrual cycle and were randomized initially to one of two monitoring protocols. In protocol A, urinary LH monitoring was used to time IUI. Urinary LH levels were determined daily with the use of commercial kits, starting on day 10 of the cycle. When urinary LH was detected, IUIs were performed daily for the next 2 days. In protocol B, ultrasound monitoring of folliculogenesis was performed until a leading follicle of ≥18 mm was noted, at which time hCG (10,000 IU) was given intramuscularly and IUIs were performed daily for the next 2 days. If no pregnancy occurred, the couple crossed over to the alternate protocol for the next cycle and continued this alternating therapy for a total of four cycles.

Main Outcome Measure(s): Pregnancy rate per cycle.

Result(s): One hundred forty-one cycles were completed. In these cycles, six pregnancies occurred, for an overall pregnancy rate of 4.26% per cycle. The pregnancy rate with LH-timed IUI was 4.29% (3/70) and that with hCG-induced ovulation was 4.23% (3/71); the difference was not statistically significant.

Conclusion(s): Timing IUI with the use of a relatively expensive and time-consuming method such as ultrasound monitoring of folliculogenesis and hCG induction of ovulation does not appear to produce an increased pregnancy rate over urinary LH monitoring of ovulation.     

Use of Hyaluronidase to Prevent Perineal Trauma During Spontaneous Births: A Randomized,Placebo‐Controlled,Double‐blind,Clinical Trial

Introduction: The purpose of this study was to compare the frequency and severity of perineal trauma during spontaneous birth with or without perineal injections of hyaluronidase (HAase). Methods: A randomized, placebo‐controlled, double‐blind clinical trial was conducted in a midwife‐led, in‐hospital birth center in São Paulo, Brazil. Primiparous women (N = 160) were randomly assigned to an experimental (n = 80) or control (n = 80) group. During the second stage of labor, women in the experimental group received an injection of 20.000 turbidity‐reducing units of HAase in the posterior region of the perineum, and those in the control group received a placebo injection. The assessment of perineal outcome was performed by 2 independent nurse‐midwives. A 1‐tailed Fisher exact test was performed, and a P value < .025 was considered statistically significant. Results: Perineal integrity occurred in 34.2% of the experimental group and in 32.5% of the control group, which was not a statistically significant difference (P= .477). First‐degree laceration was the most common trauma in the posterior region of the perineum in women in both groups (experimental = 56%, control = 42.6%). Severe perineal trauma occurred in 28.9% of the experimental group and 38.8% of the control group, which also was not a statistically significant difference (P= .131). The depth of second‐degree perineal lacerations in the experimental and control groups, measured by the Peri‐Rule, was 1.9 cm and 2.3 cm, respectively. An episiotomy was performed in 11 women (experimental group = 3, control group = 8), and 4 (all in control group) had third‐degree lacerations. Discussion: The use of injectable HAase did not increase the proportion of intact perineum and did not reduce the proportion of severe perineal trauma in our sample.