Management of congenital hypogonadotropic hypogonadism in females.

This review explores the challenges in the diagnosis of hypogonadotropic hypogonadism, the transition of care from paediatric to adult care and the considerable health implications of this condition. The role gynaecologists and general practitioners have in managing hormone replacement therapy and reproductive potential is also highlighted. The fertility treatment options, which include ovulation induction with gonadotrophins and in-vitro fertilisation, are discussed in detail along with highlighting the fact that anovulation and markers of low ovarian reserve prior to priming treatment may not be reflective of poor reproductive potential. The holistic management of women with hypogonadotropic hypogonadism is still not standardised and evidence for subfertility management is scarce. This review aims to highlight this concern and provide guidance by evaluating current evidence.

Adjuvant treatment strategies in ovarian stimulation for poor responders undergoing IVF: a systematic review and network meta-analysis.

BACKGROUND: Despite great advances in assisted reproductive technology, poor ovarian response (POR) is still considered as one of the most challenging tasks in reproductive medicine. OBJECTIVE AND RATIONALE: The aim of this systemic review is to evaluate the role of different adjuvant treatment strategies on the probability of pregnancy achievement in poor responders undergoing IVF. Randomized controlled trials (RCTs) comparing 10 adjuvant treatments [testosterone, dehydroepiandrosterone (DHEA), letrozole, recombinant LH, recombinant hCG, oestradiol, clomiphene citrate, progesterone, growth hormone (GH) and coenzyme Q10 (CoQ10)] were included. SEARCH METHODS: Relevant studies published in the English language were comprehensively selected using PubMed, Embase and the Cochrane Central Register of Controlled Trials (CENTRAL) until 11 July 2018. We included studies that investigated various adjuvant agents, including androgen and androgen-modulating agents, oestrogen, progesterone, clomiphene citrate, GH and CoQ10, during IVF treatment and reported subsequent pregnancy outcomes. The administration of GnRH analogs and gonadotrophins without adjuvant treatment was set as the control. We measured study quality based on the methodology and categories listed in the Cochrane Collaboration Handbook. This review protocol was registered with PROSPERO (CRD42018086217). OUTCOMES: Of the 1124 studies initially identified, 46 trials reporting on 6312 women were included in this systematic review, while 19 trials defining POR using the Bologna criteria reporting 2677 women were included in the network meta-analysis. Compared with controls, DHEA and CoQ10 treatments resulted in a significantly higher chance of clinical pregnancy [odds ratio (OR) 2.46, 95% CI 1.16 to 5.23; 2.22, 1.08-4.58, respectively]. With regard to the number of retrieved oocytes, HCG, oestradiol and GH treatments had the highest number of oocytes retrieved [weighted mean difference (WMD) 2.08, 0.72 to 3.44; 2.02, 0.23 to 3.81; 1.72, 0.98 to 2.46, compared with controls, respectively]. With regard to the number of embryos transferred, testosterone and GH treatment led to the highest number of embryos transferred (WMD 0.72, 0.11 to 1.33; 0.67, 0.43 to 0.92; compared with controls, respectively). Moreover, GH resulted in the highest oestradiol level on the HCG day (WMD 797.63, 466.45 to 1128.81, compared with controls). Clomiphene citrate, letrozole and GH groups used the lowest dosages of gonadotrophins for ovarian stimulation (WMD 1760.00, -2890.55 to -629.45; -1110.17, -1753.37 to -466.96; -875.91, -1433.29 to -282.52; compared with controls, respectively). CoQ10 led to the lowest global cancelation rate (OR 0.33, 0.15 to 0.74, compared with controls). WIDER IMPLICATIONS: For patients with POR, controlled ovarian stimulation protocols using adjuvant treatment with DHEA, CoQ10 and GH showed better clinical outcomes in terms of achieving pregnancy, and a lower dosage of gonadotrophin required for ovulation induction. Furthermore, high-level RCT studies using uniform standards for POR need to be incorporated into future meta-analyses.

The effect of physical activity on reproductive health outcomes in young women: a systematic review and meta-analysis.

BACKGROUND: In the context of increasing rates of overweight and obesity in young adult women, and the increasing numbers of women seeking help for fertility problems, it is important to understand whether physical activity (PA) could help with management of reproductive health problems, with or without weight loss. OBJECTIVE AND RATIONALE: The primary aim of this systematic review and meta-analysis was to assess the effects of PA on selected reproductive health outcomes in young adult women, in order to inform best practice advice for women in terms of promoting fertility and reproductive health in young adulthood. SEARCH METHODS: An electronic search of PubMed, EMBASE, MEDLINE, Cumulative Index to Nursing and Allied Health Literature, PsycINFO, Web of Science, SportDiscus, and Cochrane was performed for studies published between January 2000 and May 2018. Keywords and Medical Subject Headings terms related to PA, reproductive health, and weight gain were used. Studies were selected if they were intervention studies, if PA was delivered as part of an intervention to pre-menopausal women, and if any reproductive health outcome was reported. Quality analysis was performed using the Tool for the assEssment of Study qualiTy and reporting in EXercise. OUTCOMES: Eighteen studies, with a mix of four types of study design (4 randomized controlled trials (RCTs), 11 randomized comparison trials, 2 non-randomized comparison trials, and 1 single-arm clinical trial), were identified. Comparisons included fertility treatment (four studies) and common treatments for women with polycystic ovary syndrome (PCOS) symptoms (nine studies). Pooled analysis of data from three of the four studies with a control group showed higher pregnancy [risk ratio (RR) 2.10, 95% CI (1.32, 3.35); three studies] and live birth [RR 2.11, 95% CI (1.02, 4.39); two studies] rates in the intervention groups compared with non-therapy controls. Aggregated data from the fertility treatment comparative studies (i.e. those that compared PA with standard fertility treatment such as clomiphene, gonadotrophins, and/or IVF) showed no significant intervention differences: RR 1.46, 95% CI (0.87, 2.45) for clinical pregnancy (four studies) and RR 1.09, 95% CI (0.56, 2.12) for live births (two studies). Pooled analysis from the comparison trials that used pharmaceutical or dietary treatment for PCOS as comparison showed higher pregnancy rates [RR 1.59, 95% CI (1.06, 2.38); five studies] and live birth rates [RR 2.45, 95% CI (1.24, 4.83); two observations] in the PA intervention groups than in the comparison groups. Analysis of other outcomes, such as ovulation rates, menstrual regularity, and conception rates, showed no differences between the PA intervention and comparison groups. WIDER IMPLICATIONS: There is emerging evidence from RCT that PA may improve pregnancy rates in women with reproductive health problems. Comparative studies indicate that PA intervention may be as effective as other commonly used clinical intervention strategies for improving reproductive health outcomes. While the type, intensity, frequency, and duration of optimal PA intervention, and the role of PA independent of weight loss, remain unclear, these preliminary findings suggest that PA may be an affordable and feasible alternative or complementary therapy to fertility treatments.

Ovarian Stimulation Protocol in IVF: An Up-to-Date Review of the Literature.

The Assisted Reproductive Technology (ART) was born in order to help couples with infertility issues in having a baby. The first treatments of IVF used the spontaneous cycle of the women, with the retrieval of only one oocyte. Further studies have shown that it is possible to induce ovulation by administrating gonadotropins during the menstrual cycle, in order to obtain a higher number of oocytes. Many stimulation protocols have been introduced for controlled ovarian hyperstimulation of patients undergoing in vitro fertilization treatment. This review describe the different stimulation protocols using follicle-stimulating hormone (FSH) in combination with Gonadotropin releasing hormone (GnRH) either agonist or antagonist, oral supplementations and ovarian triggering. Using GnRH antagonist protocols have been demonstrated to improve significantly the clinical pregnancy rates for expected poor and high-responders, and in those women at high risk of developing ovarian hyperstimulation syndrome (OHSS). Two meta-analyses showed a better outcome in terms of the live birth rate when highly purified human menopausal gonadotropin (HMG) was used for ovarian stimulation compared with recombinant follicle stimulating hormone (rFSH) in the GnRH agonist long protocol. One of the most efficient stimulation protocol is the use of a combined protocol of human derived urinary FSH (uFSH) and rFSH. Combined protocol has resulted in a significant increase in the proportion of mature metaphase II oocytes and grade 1 embryos when compared to either rFSH or uFSH alone. A significantly higher delivery rate was achieved in rFSH+uFSH compared to the other protocols in poor and normal responders. Studying the combination of melatonin with myo-inositol and folic acid has also showed a higher percentage of mature oocytes in the melatonin group and a higher percentage of G1 embryos as well. However, It remains a crucial step to confirm the efficacy of such protocols for clinical application and it is still needs to comparison studies on larger scale with more focused on the differences in patients' response criteria and additional confounding variables, in order to draw more defined conclusions.

Protein modification as oxidative stress marker in follicular fluid from women with polycystic ovary syndrome: the effect of inositol and metformin.

PURPOSE: The purpose of this study was to evaluate the oxidative stress status (OS) of follicular fluid (FF) and the oocyte quality in women with polycystic ovary syndrome (PCOS) undergoing different ovarian stimulation protocols. METHODS: FF samples were collected after gonadotropin administration in association or not with metformin or D-chiro-inositol (DCI). OS status was then evaluated by checking the follicular fluid protein oxidation profile after specific labeling of aminoacidic free-SH groups, and two-dimensional electrophoresis followed by qualitative and semiquantitative analysis. Oocyte quality was assessed by international morphological criteria. RESULTS: Our data indicated that both treatments, even if to different extent, recovered a significantly high level of free-SH groups in FF proteins of PCOS women clearly indicating a decrease of OS level with respect to that found in FF samples from gonadotropins alone treated women. A higher number of good quality MII oocytes was also observed in DCI (P < 0.05) or metformin (P < 0.05) study groups in comparison to untreated control group. CONCLUSION: A natural supplement and a drug both showed a statistically significant positive effect on follicular milieu by decreasing the oxidative damage on FF proteins, as well as in recovering good quality oocytes.

Premature ovarian insufficiency: how to improve reproductive outcome?

Premature ovarian insufficiency (POI) is a life-changing condition that affects women in their reproductive age. The condition is not necessarily permanent but is associated with intermittent and unpredictable ovarian activity. Hence, spontaneous pregnancies have been reported to be 5-10%. However, pregnancy in patients with POI is still unlikely and rare. Although, there are reviews on POI in the literature, there is a lack of reports which focus on how to improve the reproductive outcome of these women who wish to conceive spontaneously or use assisted conception with their own oocytes. We found that there is no conclusive evidence of which treatment is optimal for women with POI who wish to conceive using their own gametes. However, one could surmise that it is important to lower gonadotropin levels into the physiological range before embarking on any treatment, even if natural conception is the only choice for the woman/couple. In the future, multi-center, randomized, double-blind, placebo-controlled trials should be carried out, which may entail recruitment of patients from various centers nationally and internationally to increase the sample size and therefore achieve a powered study. This may standardize the treatment of women with POI who wish to conceive and ultimately have their biological child.

Male reproductive endocrinology: when to replace gonadotropins.

Infertility is generally defined as a couple's inability to conceive after 1 year of unprotected intercourse. When infertile couples seek assistance, a male factor will be identified half of the time. Once the male has been evaluated, there are four main categories to describe his infertility: (1) idiopathic, (2) post-testicular/obstructive, (3) primary-where the Sertoli and/or Leydig cells of the testis fail, and (4) secondary-where there is a problem with the hypothalamus and/or pituitary. The last, hypogonadotropic hypogonadism (HH), accounts for up to 2% of infertile men. HH is either congenital or acquired and usually can be successfully treated by medical intervention. This review will focus on the hypothalamus-pituitary-gonadal axis, specific defects of this coordination center, and potential interventions for improving male-factor fertility.

Effects of Chinese medicines for tonifying the kidney on DNMT1 protein expression in endometrium of infertile women during implantation period.

OBJECTIVES: The purpose of this study was to explore the effects of Erzhi Tiangui Granule (ETG) on DNA methyltransferases (DNMT) 1 protein expression in endometrium of infertile women with Kidney-yin Deficiency syndrome. METHODS: A randomized, double-blinded, placebo-controlled clinical trial was conducted. Sixty-six (66) infertile patients who had Kidney-yin Deficiency syndrome and who were to undergo in vitro fertilization-embryo transfer (IVF-ET) were randomly assigned to either a treatment group or a control group according to a random table. Besides gonadotropin (Gn) therapy in both groups, the treatment group received ETG for 3 menstrual cycles before IVF, and the control group received placebo granules. The ETG and the placebo granules were made with similar color and shape, as well as in the same packaging. The scores of the Kidney-yin Deficiency syndrome were assessed. Other outcome measures included the dosage and duration of Gn, the number of retrieved oocytes, the rate of high-quality oocytes, the rate of high-quality embryos, the fertilization rate, and the clinical pregnancy rate. DNMT1 protein expression in the endometrium was measured in the midluteal phase. RESULTS: The difference in the syndrome score change before and after treatment between the two groups was statistically significant (p<0.05). The dosage and duration of Gn were significantly lower in the treatment group than those in the control group (p<0.05). The high-quality oocyte and embryo rates, and clinical pregnancy rate were all higher in the treatment group than those in the control group (p<0.05). The fertilization rate was not significant when compared to the placebo group. No difference was found in the number of retrieved oocytes between the two groups. The DNMT1 protein expression in the endometrium was much more abundant in the treatment group than that in the control group (p<0.05). CONCLUSIONS: For the infertile patients undergoing IVF, the Chinese recipe for tonifying the Kidney as an adjunct treatment could reduce Gn dosage and treatment duration, alleviate clinical symptoms, and improve the clinical pregnancy rate. The increased level of DNMT1 protein expression after treatment may lead to enhanced endometrial receptivity. This finding may explain the improvement in clinical pregnancy rate.

An evidence-based perspective to the medical treatment of male infertility: a short review.

INTRODUCTION: Evidence-based medicine (EBM) is the integration of best research evidence with clinical expertise and patient preferences and values. AIM: This narrative review aims to assist the physicians to make informed decisions based on the best available evidence in the area of male infertility and the patients' own preferences and values. METHODS: In this review we present the current state of knowledge and uncertainties about the medical management of male infertility. We describe the best available evidence from systematic reviews, randomized controlled studies and observational studies where appropriate. RESULTS: Data from the literature suggest that gonadotropin treatment of male infertility can lead to a significant increase in pregnancy rates, however larger studies are needed to confirm such findings. Studies including combinations of antiestrogens, antioxidants and androgens are promising but need confirmation with further research. CONCLUSIONS: Most current combination therapies consist of orphan medications without industry support. Andrology research centers and other dedicated departments and units need to conduct randomized controlled trials of sufficient duration, sample number and robust design for groups most likely to benefit from antiestrogens, L-carnitine, antioxidants, and combination therapy. The ease of administration, low cost and mild side effects of antiestrogens justify their utility despite insufficient evidence of effect as monotherapies. Randomized controlled trials assessing other forms of medical therapy and combination therapy are available but are still in the preliminary stages.

[Evidence-based drug therapy for male infertility]. / Evidenzbasierte medikamentöse Therapieansätze der Infertilität.

Evidence-based drug therapy for male infertility is often difficult because 30% of all cases of male infertility are classified as idiopathic, and another 30% need surgical treatment. Without knowledge of the underlying pathology, there is no foundation for a specific and causal treatment. Most of the currently used drug therapies are empirical at best; moreover, many of the studies on drug treatment for male infertility do not fulfill the required standards of evidence-based medicine (randomized, prospective, placebo-controlled), and the statistical endpoints used (sperm quality, pregnancy rate, baby take-home rate) are not uniform. This article, which is based on a literature survey and the current guidelines concerning drug therapy for male infertility, covers the most common treatment options. Regarding the currently insufficient scientific data for drug therapy and dietary supplements on male infertility, there is a demand for critical indications that take into consideration the possible side effects and the treatment costs. In the case of insufficient drug therapy for male infertility, reproductive medicine seems to be promising.

Polycystic ovary syndrome in asian women.

There is substantial heterogeneity of symptoms and signs among women with polycystic ovary syndrome (PCOS). In addition to different diagnostic criteria used, the ethnic background of women with PCOS may affect the clinical, hormonal, and metabolic characteristics of this condition. We present here studies related to the clinical, hormonal, and metabolic characteristics and response to the treatment of PCOS in Asia, which may be different from those in Western countries. It is important to take into consideration the ethnic background of patients in future studies related to PCOS.

Medical and surgical management male infertility.

Male infertility is the result of a variety of highly treatable conditions. The critical step in treating male infertility is to evaluate properly every male partner of an infertile couple and to generate the proper treatment strategy. There are many medical and surgical options that can help most couples overcome male factor infertility. Male infertility can most easily be broken down into problems of sperm production (testicular dysfunction) and problems of sperm transport (obstruction). When applicable, medical therapies are used as an initial strategy to improve sperm production or as a preliminary therapy to boost production transiently in anticipation of a surgical sperm retrieval attempt. A range of surgical options is available to correct varicoceles, reconstruct the obstructed system, or retrieve sperm for assisted reproduction.

Surgical treatment in polycystic ovary syndrome.

PURPOSE OF REVIEW: The purpose of this review is to provide a critical summary of current knowledge on the role and effectiveness of ovarian surgery in the treatment of polycystic ovary syndrome. RECENT FINDINGS: Clomiphene citrate is used as a first-line treatment for ovulation induction in infertile anovulatory patients with polycystic ovary syndrome. In clomiphene citrate-resistant women, other treatment modalities such as laparoscopic electrocautery or ovulation induction with gonadotropins have been proposed as alternative therapies. Although gonadotropin treatment and laparoscopic ovarian drilling have demonstrated similar reproductive outcomes, laparoscopic ovarian drilling has some advantages over gonadotropin treatment such as lower cost per pregnancy, improvement in menstrual regularity, and better long-term reproductive performance. On the other hand, knowledge about the pathogenesis of polycystic ovary syndrome has been growing and insulin-sensitizing drugs have gained popularity as a new treatment option. SUMMARY: According to current data, metformin has gained popularity as first-line management in clomiphene citrate-resistant women with polycystic ovary syndrome. If ovulation does not occur within several months after treatment with metformin, after the evaluation of all pros and cons related to each treatment, laparoscopic ovarian drilling or gonadotropins may be considered as an effective option according to patient choice.

Surgical treatment of polycystic ovary syndrome associated with infertility.

Laparoscopic ovarian drilling is a relatively simple procedure performed by minimal access and usually on an outpatient basis. It provides an alternative treatment option for polycystic ovary syndrome (PCOS) patients anovulatory to clomiphene citrate. The mechanism of action of laparoscopic ovarian drilling is unclear; its beneficial effect is apparently due to destruction of the androgen-producing stroma. The procedure appears to have little or no effect on insulin sensitivity and lipoprotein profile. The majority (56-94%) of PCOS patients who are clomiphene citrate resistant ovulate after drilling, and at least half of them go on to achieve a pregnancy. Predictive factors for pregnancy are younger age and lower body mass index. The endocrine changes resulting from ovarian drilling last for an extended period of time. Exogenous gonadotrophin treatment and laparoscopic ovarian drilling appear to yield comparable ovulation and pregnancy rates; however, multiple pregnancy is rare with drilling. There are several complications associated with the procedure, including post-operative periadnexal adhesion formation. Alternative treatment options, including lifestyle modification (diet and exercise) and metformin, may well reduce the need for ovarian drilling in well-selected cases. Progress in understanding of this complex syndrome and effective new treatments will further diminish the need for surgery.

Management strategies for male factor infertility.

Although modern assisted reproduction techniques contribute a lot to overcoming severe male factor infertility, application of these methods in every infertile couple would represent an over-treatment. Therefore, conventional treatment modalities are still the first approach to male fertility disorders. Apart from assisted reproduction techniques, these include surgical procedures and the administration of drugs. Causal treatment regimens of proven effectiveness are only available for patients with infertility resulting from hypogonadotrophic hypogonadism. Drug treatment of retrograde ejaculation is also effective. Inconsistent results have been obtained with empirical treatment including antiestrogens, androgens, aromatase-inhibitors, mast cell blockers, zinc and pentoxifylline. Anti-inflammatory and immunosuppressive therapy as well as treatment with antioxidants in the presence of reactive oxygen species has not yet been demonstrated to be effective by controlled studies but represent at least a rational approach which should be investigated more thoroughly. High dosage administration of follicle stimulating hormone aimed particularly at improving disturbed sperm structures, and the combination of tamoxifen with androgens, may be promising developments. A careful diagnostic work-up is necessary before any andrological treatment is commenced so that adequate treatment options can be selected for individual patients.

Poor ovarian response to gonadotrophin stimulation the role of adjuvant treatments.

Poor ovarian response to gonadotrophin stimulation represents a clinical problem in in vitro fertilization practice. Women showing poor ovarian response are a heterogeneous group, many of whom have a reduced ovarian reserve and consequently a lower pregnancy potential. Various management strategies have been proposed to improve ovarian response to gonadotrophins, but these have met with limited success. Adjuvant treatments aim to potentiate the effect of exogenous follicle-stimulating hormone. In separate, randomized, placebo-controlled trials low-dose dexamethasone and aspirin have been shown to reduce the incidence of poor response in an initial stimulation cycle. Preliminary studies using pyridostigmine and L-arginine in established poor responders are encouraging but require confirmation in adequately powered studies. Evidence from randomized controlled trials does not support the use of adjuvant growth hormone or growth hormone-releasing hormone in poor responders without overt growth hormone deficiency. The mechanisms of action of adjuvant treatments require further investigation.

Aromatase activity of human granulosa cells in vitro: effects of gonadotrophins and follicular fluid.

The aim of this study was to assess whether human dominant follicular fluid has the ability to modulate aromatase activity and/or granulosa cell proliferation. Dominant follicular fluid was obtained by laparoscopy before the luteinizing hormone surge in naturally cycling women while granulosa cells used in the tests were obtained from in-vitro fertilization patients. Aromatase was measured by the tritiated water release assay, following a 48 h incubation with follicular fluid and serum, and expressed for 5x10(4) granulosa cells. The effects of a range of follicular fluid or serum concentrations (2.5, 5, 10 and 20%) were compared. A decrease in aromatase activity was observed when high follicular fluid concentrations (20%) (P < 0.01) were added. Low concentrations (2.5%) of follicular fluid significantly increased cell proliferation (P < 0.01) as compared to basal values (0%). No further stimulation was however observed when concentrations increased up to 20%. Further characterization of these compounds is required to understand how they may modulate maturation of the dominant follicle.