After fresh embryo transfer, the remaining embryos were cultured to blastocysts Day 5 or 6 before vitrification.
Frozen-thawed embryo transfer may be applied to either artificial or natural cycles. Clinical pregnancy was defined as intrauterine pregnancy with at least one fetus with a positive heartbeat at 6 weeks of gestation or later.
The clinical pregnancy rate CPR and live birth rate LBR referred to the cumulated outcome after transferring all embryos from the studied stimulating cycle. Secondary outcomes included the number of oocytes retrieved, mature oocytes, two-pronuclear zygotes, and embryos.
The data analysis was carried out using SPSS The t -test for independent samples or the Mann-Whitney U -test were used as appropriate to compare continuous variables by group. The chi-squared test was used to compare categorical variables by group. Repeated-measures analysis of variance was used for measuring repeated longitudinal data. Their demographic characters were shown in Table 1. The two groups were compared in terms of baseline characteristics and pregnancy outcomes Table 1.
Figure 1. Flowchart regarding patients' inclusion and exclusion. Table 1. Nearly half of the patients were distributed in Group II. Therefore, we applied Group II as a dummy variable. It turned out the last two factors basal E 2 and BMI were not statistically significant. The results revealed that a higher basal PRL was related to a better rate of cumulated clinical pregnancy and live birth. Table 2. Multifactor analysis of the relationship between basal PRL and pregnancy outcomes.
There were 1, cases with positive cumulated clinical pregnancy and 1, cases with cumulated live birth. The PRL levels of patients with positive pregnancy outcomes were significantly higher at all measurement points than those of patients with negative results.
Moreover, a sharper spike was observed in groups with positive clinical pregnancy or live birth. Table 3. Comparison of serum PRL levels between different pregnancy outcomes at different time points by repeated-measures analysis of variance. Hyperprolactinemia has long been considered detrimental to fertility due to its effect on blocking LH secretion, leading to anovulation, or luteolysis 2.
However, in IVF, oocyte maturation is induced by hCG trigger, and sufficient luteal phase support is guaranteed by progesterone supplements. Therefore, IVF procedures provide an ideal opportunity to observe the potential effect of PRL on reproduction in comparison to suppression of gonadotropins. In cycles with better pregnancy outcomes, will there be greater increase of PRL throughout ovarian stimulation basal state, hCG day, and the day after hCG triggering?
Approximately a quarter of patients with hyperprolactinemia are shown to have macroprolactinemia. Women with macroprolactinemia may have no symptoms despite their elevated serum PRL levels due to inactive macroprolactin 5. That is to say, some asymptomatic hyperprolactinemia may be caused by macroprolactinemia; thus, such patients may not need dopamine agonist administration before IVF treatment.
However, macroprolactin was not measured in our study. Future research should study macroprolactin and the proportion of active PRL levels. Kamel et al. T1 and T1 vs. Additionally, higher PRL levels were associated with higher embryo quality 6.
Doldi et al. Thus, the PRL levels were significantly lower than those of the control group who did not receive cabergoline. However, there was no improvement of CPR in patients treated with cabergoline adding the effect of rFSH consumption Previous research by Mendoza et al. Oogenesis is a complicated process involving oocytes and the granular cell cumulus actively exchanging signals within the circulating body fluid.
Nakamura et al. In contrast, higher mature rates were found when exogenous PRL was added to pre-antral follicle cultures of the IVF system It could be a possible hypothesis that a certain PRL level guarantees the accomplishment of meiosis. Although there was no statistical significance, there was an increasing trend of the implantation rate from Since PRL improved oogenesis and embryonic development, some researchers have tried to improve the IVF outcomes by prescribing bromocriptine to patients with a history of recurrent implantation failure until the initiation day of rFSH.
Treatment of infertility associated with PCOS has changed in the last decade due to the introduction of new medications such as insulin-sensitizing drugs, aromatase inhibitors, gonadotropin treatment etc.
Bracero , Urman, , Escobar-Morreale, There were several reasons of hyperprolactinemia: pituitary adenoma; drug-induced hyperprolactinemia, or macroprolactinemia. The authors concluded that hyperprolactinemia is not a clinical manifestation of PCOS.
Filho, Some medications can cause higher levels of prolactin to be produced. The most common medications that do this are known as anti-psychotic medications. The second- and thirdgeneration antipsychotics have a weaker affinity for D2 dopamine receptors, thus hyperprolactinemia is less common when such medication is used.
Uzun et al. The risk of side effects caused by antipsychotics is individual and it does not depend solely on the therapeutic dose and may have influence on some predisposing conditions. Some types of anti-depressants, serotonin reuptake inhibitors, SRIs fluvoxamine; fluoxetine; paroxetine, duloxetine etc.
A high prolactin level can sometimes be related to physical stress. Even drawing blood can by itself cause someone to produce and immediate prolactin-release. PRL eleveation can also detected in response to strong or sudden external stimuli in general, such as stressful environmental conditions, or can be related to physchological reasons.
Harrison, ; Cepisky, On the other hand, anxiety and irritability maybe a result of hyperprolactinemia. Endocrine abnormalities are frequently associated with a wide range of psychological symptoms. These symptoms may reach the level of psychiatric illness mainly mood and anxiety disorders or just being identified by the subclinical forms of assessment provided by the Diagnostic Criteria for Psychosomatic Research DCPR. Long-standing endocrine disorders may imply a degree of irreversibility of the pathological process.
Endocrine treatment may cause even the worsening of psychological symptoms. The methodology and assessment score provided by DCPR tests have been demonstrated to be a valuable tool for psychological assessment in endocrine disease from diagnostic to follow-up periods. Sonino In clinical environment the variability of PRL concentration in random estimations underline the need for special testing to rule out stress-related hyperprolactinemia and diagnostic pitfalls.
It was recommended by the results, that two or three serial PRL determinations in resting conditions provide more reliable results Muneyyirci-Delale, In experimental conditions, hyperprolactinemia and stress interact differentially according to the length of the stimuli and that is connected to the immune response modulated by PRL.
Surgical or restraint stress induce marked 2x- 4x increase of plasma PRL of control rats, but interestingly did not change the PRL levels of hyperprolactinemic rats. In both cases the plasma glucose levels reported elevated Reis, There is evidence that several external stress-factors may contribute to the occurrence of hyperprolactinemia.
In theory, stress might have been involved in facilitation of a clonal proliferation of a single mutated cell and cause prolactinomas. Verhelst, ; Freeman, ; Fava, Prolactin is a pituitary-derived hormone that plays an important role in a variety of reproductive functions. It is an essential factor for normal production of breast milk following childbirth.
Additionally, prolactin negatively modulates the secretion of pituitary hormones responsible for gonadal function, including luteinizing hormone and follicle-stimulating hormone. Clnincally significant hyperprolactinemia may result in hypogonadism, infertility, and galactorrhea, or in some cases it may remain asymptomatic for a long period. Klibanski The most commonly cited indications for treatment of microprolactinomas is infertility and hypogonadism. Hypogonadism and infertility associated closely with the treatment: DA agonists can restore normal PRL levels and consequently the normal gonadal function.
Gillam ; Wang Prolactin is under dual regulation by hypothalamic hormones delivered through the hypothalamic—pituitary portal circulation. The differential diagnosis and causes of pathological hyperprolactinemia are summarized in Figure 1. The predominant signal is inhibitory, preventing prolactin release, and is mediated by the neurotransmitter dopamine.
The stimulatory signal is mediated by the hypothalamic TRH. The balance between the two opposite signals determines the amount of prolactin released from the anterior pituitary gland Verhelst; Prolactin is under dual control from the hypothalamus. The first steps in cases of signs of hyperprolactinemia should be a critical diagnosis, as discussed above, may involve dynamic testings, assessment for macroprolactinemia and further laboratory tests to eliminate false positive or negative results.
The major steps of diagnosis of hyperprolactinemia is summarized in Figure 2. Approach to diagnosis of hyperprolactinemia. Specific recommendations for diagnosis of hyperprolactinemia include the following Melmed :. A single measurement of serum prolactin level can confirm the diagnosis if the level is above the upper limit of normal and the serum sample was obtained without excessive venipuncture stress. Dynamic testing of prolactin secretion is not recommended to diagnose hyperprolactinemia.
When there is a discrepancy between a very large pituitary tumour and a mildly elevated prolactin level, serial dilution of serum samples is recommended to eliminate the "hook effect," or an artifact that can occur with some immunoradiometric assays leading to a falsely low prolactin value.
Specific recommendations for management of drug-induced hyperprolactinemia are as follows Melmed :. In a symptomatic patient with suspected medication-induced hyperprolactinemia, the drug should be discontinued for 3 days or an alternative drug substituted, and the serum prolactin measurement should then be repeated.
However, the patient's physician should be consulted before an antipsychotic agent is discontinued or substituted. If the drug cannot be discontinued and the onset of the hyperprolactinemia does not coincide with starting therapy, magnetic resonance imaging MRI of the pituitary gland may distinguish medication-induced hyperprolactinemia from symptomatic hyperprolactinemia caused by a pituitary or hypothalamic mass.
Patients with asymptomatic medication-induced hyperprolactinemia should not be treated. Estrogen or testosterone can be used in patients with long-term hypogonadism hypogonadal symptoms or low bone mass caused by medication-induced hyperprolactinemia.
If it is not possible to stop the drug causing medication-induced hyperprolactinemia, cautious administration of a dopamine agonist should be considered, in consultation with the patient's physician. As noted above, prolactin levels can often be corrected by stopping suspected medication or switching to a different medication type. Correction of hypothyroidism is also effective and specific to reduce PRL levels.
If prolactin levels are persistently high, they can be effectively treated with a group of medications known as dopamine agonists. According to our clinical practice patients with macroadenoma suggested to undergo transsphenoidal pituitary surgery.
Medical treatment is given to the subjects with microadenoma, persistent postoperative hyperprolactinemia, and to those cases of hyperprolactinemia when it is caused by other medications. From the available mediactions Bromocriptine 2. Parlodel is an effective and inexpensive medication for high prolactin levels. Parlodel is usually taken at bedtime with a snack. This is because Parlodel will occasionally cause dizziness or stomach upset, so taking it before sleep and with food will reduce those side effects.
Generally with time, the side effects stop anyway. The prolactin levels can be rechecked in about three weeks. If the levels are still elevated the dose can be increased or a different medication can be tried. The administration of Parlodel can be stopped upon diagnosis of pregnancy.
However, if a woman has a macroadenoma, Parlodel should be continued through pregnancy and delivery. Due to the side effects, some women can not tolerate Parlodel. For these women, they may try alternatives, e. Because it is more expensive, cabergoline is not usually the first choice for treatment of high prolactin levels. It is usually used when Parlodel is ineffective or a woman cannot tolerate the side effects. Cabergoline is a longer acting medication. It is usually given twice a week instead of every day.
The Endocrine Society has released a new clinical practice guideline for the diagnosis and treatment of patients with hyperprolactinemia Melmed, The new recommendations for management of elevated levels of the PRL, which is associated with infertility, low sex drive, and bone loss, are listed.
Dopamine agonist therapy is recommended to reduce prolactin levels and tumor size and to restore gonadal function in patients with symptomatic prolactin-secreting microadenomas or macroadenomas.
Compared with other dopamine agonists, cabergoline is more effective in normalizing prolactin levels and in shrinking pituitary tumours. Dopamine agonists are not recommended for asymptomatic patients with microprolactinomas. However, patients with microadenomas who have amenorrhea can be treated with a dopamine agonist or oral contraceptives.
In patients treated with dopamine agonists for at least 2 years who no longer have elevated serum prolactin levels or visible tumour on MRI, careful clinical and biochemical follow-up therapy may be tapered and perhaps discontinued.
Specific recommendations for management of resistant and malignant prolactinoma are as follows Melmed :. For symptomatic patients in whom normal prolactin levels are not achieved or who have significant shrinking of the tumour size while receiving standard doses of a dopamine agonist, the dose should be increased rather than referring the patient for surgery. Symptomatic patients with prolactinomas who cannot tolerate high doses of cabergoline or who are unresponsive to dopamine agonist therapy should be offered trans-sphenoidal surgery.
Patients intolerant of oral bromocriptine may respond to intravaginal administration. Radiation therapy is recommended for patients in whom surgical treatment fails or for those with aggressive or malignant prolactinomas.
Specific recommendations for management of prolactinoma during pregnancy are as follows Melmed :. Women with prolactinomas should discontinue dopamine agonist therapy as soon as pregnancy is recognized, except for selected patients with invasive macroadenomas or adenomas abutting the optic chiasm.
Unless there is clinical evidence for tumour growth, such as visual field impairment, routine use of pituitary MRI during pregnancy is not recommended in patients with microadenomas or intrasellar macroadenomas.
Women with macroprolactinomas that do not shrink during dopamine agonist therapy or women who cannot tolerate bromocriptine or cabergoline should be counselled regarding the potential benefits of surgical resection before attempting pregnancy.
Bromocriptine therapy is recommended in patients who experience symptomatic growth of a prolactinoma during pregnancy. Hyperprolactinemia has been proposed to block ovulation through inhibition of GnRH release. Your doctor may also perform a physical exam to find any obvious causes or any breast discharge.
If levels are still high after the second check, your doctor may order a magnetic resonance imaging MRI scan of the brain to check for a tumor of the pituitary gland. The treatment depends on the cause. If no cause is found or you have a tumor of the pituitary gland, the usual treatment is medicine. Hypothyroidism is treated with thyroid replacement medicine, which should also make prolactin levels return to normal.
If your regular medicine is the reason for your high prolactin levels, your doctor will work with you to find a different medicine or add one to help your prolactin levels go down. The most commonly used medicines are cabergoline and bromocriptine.
Your doctor will start you on a low dose of one of these medications and slowly increase the dose until your prolactin levels go back to normal. Treatment continues until your symptoms lessen or you get pregnant if that is your goal.
Usually, your doctor will stop treatment once you are pregnant. Cabergoline is taken twice a week and has fewer side effects than bromocriptine. Generally, cabergoline drops prolactin levels to normal faster than bromocriptine does. Cabergoline can cause heart valve problems when taken in high doses, but these doses are not used in women who are trying to get pregnant.
Bromocriptine and cabergoline can been used when woman is pregnant.
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