Elevated Gonadotropin Levels Research Articles

The genetics of premature ovarian failure: current perspectives.

Premature ovarian failure (POF) is a common cause of infertility in women, characterized by amenorrhea, hypoestrogenism, and elevated gonadotropin levels in women under the age of 40. Many genes have been identified over the past few years that contribute to the development of POF. However, few genes have been identified that can explain a substantial proportion of cases of POF. The unbiased approaches of genome-wide association studies and next-generation sequencing technologies have identified several novel genes implicated in POF. As only a small proportion of genes influencing idiopathic POF have been identified thus far, it remains to be determined how many genes and molecular pathways may influence idiopathic POF development. However, owing to POF’s diverse etiology and genetic heterogeneity, we expect to see the contribution of several new and novel molecular pathways that will greatly enhance our understanding of the regulation of ovarian function. Future genetic studies in large cohorts of well-defined, unrelated, idiopathic POF patients will provide a great opportunity to identify the missing heritability of idiopathic POF. The identification of several causative genes may allow for early detection and would provide better opportunity for early intervention, and furthermore, the identification of specific gene defects will help direct potential targets for future treatment.

Persistent Human Chorionic Gonadotropin After Methotrexate Treatment and an Emergency Surgical Procedure for Ectopic Pregnancy.

The case study is a 33-year-old white female with persistently elevated serum human chorionic gonadotropin (hCG) levels following methotrexate treatment and emergency surgery for ectopic pregnancy. At the time of the first methotrexate dose, the serum hCG concentration was 27,995 IU/L. The laboratory was consulted 3.5 months after the surgery, because serum hCG levels had stopped declining and had leveled off to around 80 to 90 IU/L but with negative urine pregnancy tests. Laboratory studies ruled out heterophile antibody interference and hook effect by multiple methods including analysis by different serum hCG assays, treatment with heterophile antibody blocking agents, and dilution studies. Three additional doses of methotrexate over six months were required for serum hCG concentrations to decline to undetectable levels. This case illustrates challenges that may arise with serum hCG measurements in management of ectopic pregnancies. Close collaboration between the laboratory and clinical service is key for optimal patient care.

Modern Approach in Premature Ovarian Failure

Abstract Premature ovarian failure (POF) is a condition affecting 1-2% of women younger than 40 years of age, characterized by amenorrhea, hypoestrogenism and elevated gonadotropin levels. In the last years it became a problem of social health interest as the frequency increased due to environmental factors and new, efficient methods for cancer treatment in young women. Few genes have beed identified to explain cases of POF but there are also autoimmune associated conditions and an increasing number of iatrogenic cases (chemotherapy, surgery, radiotherapy). Modern approach in POF means not only a precise etiological diagnosis, but also a correct counseling for these patients who often want to become parents, and a chance for a healthy life without the long term consequences of estrogen deprivation from an early age. In vitro fertilization (IVF) techniques can be useful for certain cases but research is needed on strategies to improve fertility for women who have follicles remaining in the ovaries.

Testicular “Hyperstimulation” Syndrome: A Case of Functional Gonadotropinoma

Gonadotropins secreting pituitary tumors tend to present as sellar mass with hypogonadism. Biologically active LH secretion by these tumors resulting in elevated testosterone is extremely rare. We report a case of a 48-year-old male patient who presented with giant pituitary tumor, elevated testosterone, and elevated levels of gonadotropins. Surgical resection of the tumor resulted in normalization of gonadotropins and fall in serum testosterone to subnormal levels in the postoperative period confirming that the tumor was secreting bioactive luteinizing hormone (LH).

HCG 産生を伴う卵黄嚢腫瘍および成熟奇形腫からなる卵巣混合型胚細胞腫瘍の 1 例

hCG 産生を伴う卵黄嚢腫瘍および成熟奇形腫からなる卵巣混合型胚細胞腫瘍の 1 例

High-intensity focused ultrasound combined with dilatation and curettage for Cesarean scar pregnancy

We describe a new technique for the management of Cesarean scar pregnancy (CSP), high-intensity focused ultrasound (HIFU) combined with dilatation and curettage (D&C), in four patients managed at our university hospital. All four had elevated serum human chorionic gonadotropin (hCG) levels and large lesions with strong peripheral color Doppler signals, indicating possible risk of profuse bleeding, and all four women wished to preserve their fertility. HIFU was performed under local anesthesia. Success of the treatment in all four cases was indicated by complete primary evacuation of the CSP and return of serum hCG to normal levels (serum hCG < 20 mIU/mL). However, one patient in whom there was a large scar defect and placental implantation underwent laparotomy to remove the trophoblastic tissue and repair the defect, although the hCG level had already returned to normal levels. HIFU, by utilizing ultrasound energy to heat tissue at a focal point, is able to stop embryonic cardiac activity and leads to a rapid reduction in serum hCG levels. Subsequent D&C under hysteroscopic guidance enables complete removal of products of conception following the HIFU procedure.

Ovarian complete hydatidiform mole: case study with molecular analysis and review of the literature

Ectopic complete molar pregnancy in the ovary is an exceptionally rare event. Here we present a case of ovarian complete hydatidiform mole in a 20-year-old gravida 2 para 1 woman. At presentation, the patient underwent excision of a hemorrhagic left ovarian cyst, with routine sections demonstrating a hemorrhagic corpus luteum with a single microscopic focus of detached atypical trophoblast, without chorionic villi. Subsequent left salpingo-oophorectomy for persistently elevated human chorionic gonadotropin led to a final diagnosis of complete hydatidiform mole arising in the ovary. The fallopian tube was unremarkable. Zygosity was determined using short tandem repeat analysis, confirming the diagnosis of monospermic complete mole. In the clinical setting of a markedly elevated human chorionic gonadotropin level and an ovarian mass, histopathologic examination is critical in distinguishing ectopic pregnancy from choriocarcinoma. Short tandem repeat analysis can be a useful adjunct to histologic diagnosis in challenging cases.

Preterm ovarian hyperstimulation syndrome presented with vaginal bleeding: a case report

Preterm ovarian hyperstimulation syndrome (POHS) is an uncommon disorder characterized by prematurity, hypogastric and upper leg swelling of various intensities, high serum estradiol and gonadotropin levels, and ovarian follicular cyst/cysts. In this paper, we present the first case of POHS presenting with vaginal bleeding. A female infant was born via spontaneous vaginal delivery at 25 weeks of gestation with a birth weight of 610 g. At 36 weeks of post-conception age, she developed breast enlargement, swelling of the clitoral hood, labia major and minor, hypogastrium and upper legs. Several weeks later, vaginal bleeding started and lasted 3 days. The vaginal bleeding continued to occur at monthly intervals. The elevated levels of gonadotropins and estrogens, vulvar swelling and cysts in both ovaries confirmed the diagnosis of preterm ovarian hyperstimulation syndrome.

High-Dose Chemotherapy With Autologous Stem Cell Support as Salvage Therapy in Recurrent Gestational Trophoblastic Disease

Gestational trophoblastic disease usually follows a molar pregnancy but can occur also after an abortion or a term pregnancy. In only 10% of cases will treatment be required; and usually, single-agent chemotherapy will suffice. In high-risk disease, the multiagent regimen EMA-CO is usually used; and if that fails, most oncologists will use the EMA-EP regimen. If this does not produce a remission, there is no unanimity of opinion as to how to proceed. Numerous salvage regimens are in current use, and some centers do not consider high-dose chemotherapy. A young woman presented 4 months after a normal spontaneous delivery with an elevated human chorionic gonadotropin level and multiple pulmonary metastases. She failed both the EMA-CO and EMA-EP regimens as well as additional standard chemotherapy. She was then treated with 4 separate courses of high-dose chemotherapy with autologous stem cell support, which produced a complete remission. Even patients with high-risk gestational trophoblastic disease are usually cured with standard chemotherapy. Patients who fail such treatment should be considered for high-dose chemotherapy.

Elevated human chorionic gonadotropin levels in patients with chronic kidney disease: Case series and review of literature

Women are often subjected to serum human chorionic gonadotropin (HCG) testing prior to diagnostic and therapeutic interventions. A positive result leads to further testing to rule out pregnancy and avoid possible fetal teratogenicity. The impact of chronic kidney disease (CKD) on HCG testing has not been studied. We report a series of 5 women out of 62 with CKD, who had a positive HCG test on routine pre-transplant screening at a single transplant center. We analyzed their case records retrospectively. Despite aggressive investigation, their elevated HCG levels remained unexplained. The positive test contributed to delays in transplantation and increased overall cost of treatment.

Does alcohol have any effect on male reproductive function? A review of literature

Although alcohol is widely used, its impact on the male reproductive function is still controversial. Over the years, many studies have investigated the effects of alcohol consumption on sperm parameters and male infertility. This article reviews the main preclinical and clinical evidences. Studies conducted on the experimental animal have shown that a diet enriched with ethanol causes sperm parameter abnormalities, a number of alterations involving the reproductive tract inhibition, and reduced mouse oocyte in vitro fertilization rate. These effects were partly reversible upon discontinuation of alcohol consumption. Most of the studies evaluating the effects of alcohol in men have shown a negative impact on the sperm parameters. This has been reported to be associated with hypotestosteronemia and low-normal or elevated gonadotropin levels suggesting a combined central and testicular detrimental effect of alcohol. Nevertheless, alcohol consumption does not seem to have much effect on fertility either in in vitro fertilization programs or population-based studies. Finally, the genetic background and other concomitant, alcohol consumption-related conditions influence the degree of the testicular damage. In conclusion, alcohol consumption is associated with a deterioration of sperm parameters which may be partially reversible upon alcohol consumption discontinuation.

Hyperreactio luteinalis in a spontaneously conceived pregnancy associated with polycystic ovarian syndrome and high levels of human chorionic gonadotropin

Abstract Aim: To report a case of hyperreactio luteinalis in a spontaneously conceived pregnancy. Patient: A 29-year-old primigravida presenting with painful multicystic ovarian lesions. Methods: Laparotomy and reconstruction of the ovaries. Main outcome measures: Successful pregnancy and delivery of a 3650 g female infant at 39 weeks, without any abnormalities. Results: Highly elevated human chorionic gonadotropin, estradiol, progesterone, testosterone, and free testosterone levels were observed. Ultrasound revealed bilaterally enlarged multicystic ovaries with several cysts of up to 9 cm in diameter. Conclusions: In this case, laparotomy appeared to be an appropriate therapy to prevent further suffering in the mother without doing harm to the fetus.

Resumption of ovarian function after 4 years of estro-progestin treatment in a young woman with Crohn’s disease and premature ovarian insufficiency: a case report

To report the long-term management of a case of premature ovarian insufficiency of unknown origin in a young woman with Crohn's disease. Here is reported the case of a 20 years old woman with Crohn's disease presenting with two years amenorrhea and FSH and LH levels of 255 mIU/ml and 182 mIU/ml respectively, who received 10 months corticosteroid treatment followed by 7 years of estro-progestin treatment. Corticosteroid treatment was ineffective in restoring patients gonadotropin levels as well as ovarian volume, while estro-progestins promoted a prompt reduction in gonadotrophin levels, which returned in the normal range after two years of treatment, as well as restoration of ovarian function, which occurred after four years of estrogens administration, as demonstrated by normal ovarian volume and ovulatory follicles at ultrasound, and by the re-establishment of regular menses after estroprogestin discontinuation. Long-term suppression of the endogenous gonadotropins using estroprogestins may be suggested as a treatment able to restore ovarian responsiveness even in patients with premature ovarian insufficiency showing highly elevated gonadotropin levels.

Abolition of endocrine dimorphism in hyperthyroid males? An argument for the positive feedback effect of hyperoestrogenaemia on LH secretion

Our aim was (i) to investigate the hypothalamo-hypophyseal-gonadal axis in hyperthyroid Indian males, (ii) to rule out the modulatory role of adrenal steroids on it and (iii) to determine if the simultaneous rise in oestradiol and luteinising hormone (LH) in hyperthyroid males is due to a positive feedback action of oestradiol on pituitary LH release. Age- and BMI-matched men were divided into two groups, I, euthyroid subjects (n = 17) and II, hyperthyroid patients (n = 12) on the basis of their thyroid hormone levels. Serum levels of thyroid-stimulating hormone, triiodothyronine, thyroxine, LH, follicle-stimulating hormone (FSH), prolactin, E(2), T, P(4), sex hormone binding globulin and dehydroepiandrosterone sulphate (DHEAS) were assayed. Mean levels of T and E(2) were approximately two times higher in group II in comparison with group I. DHEAS levels were similar in both groups ruling out any adrenal involvement. Mean serum LH level was 2.6 folds higher in group II in comparison with group I. Mean serum levels of FSH were higher in group II, it was marginally nonsignificant. On the basis of these and previous observations, we hypothesise that endocrinological dimorphism in human male and female is not rigid; a sustained rise in serum oestradiol probably induces a positive feedback action on pituitary leading to elevated gonadotrophin levels.

Turner Syndrome: Contemporary Thoughts and Reproductive Issues

Turner syndrome is a common genetic disorder that has been classically associated with a 45,X karyotype. Several X-chromosomal abnormalities have been identified in these patients, many of which involve mosaicism. These patients have variable but predictable phenotypic findings and are at risk for development of endocrine, autoimmune, and structural abnormalities. As many as 1.5% of the population with Turner syndrome may develop dissection and rupture of the ascending aorta; the presence of abnormalities of the cardiac tree and hypertension increase this risk, but their absence does not preclude it. Rupture has occurred at aortic diameters smaller than previously reported for other patient populations. Five percent or more of women with Turner syndrome may have abbreviated menstrual function before developing amenorrhea and hypergonadotropic hypogonadism. An estimated 1 to 2% of all patients may become pregnant. Only three patients with Turner syndrome (and two of them with streak ovaries) have ever been reported to become pregnant after developing amenorrhea and elevated gonadotropin levels. Pregnancy, either spontaneous or more commonly from donor oocyte, increases maternal mortality rate for these women by an estimated ≥100 fold. It appears that all Turner women are at risk of rupture; neither prior spontaneous menses nor age >30 years provides protection. In addition, the literature suggests that the physiological changes of pregnancy may increase the risk of rupture in future years after delivery for those Turner women who seemingly made it safely through pregnancy. The use of the term PRIMARY OVARIAN INSUFFICIENCY (POI) for Turner syndrome gives me some discomfort. For women with 46,XX hypergonadotropic hypogonadism, POI accurately provides the suggestion that follicular depletion is often not complete (although remissions are usually self-limiting and the vast majority of patients will not spontaneously become pregnant). I clearly understand the need to prevent any stigmatization to patients unfortunately diagnosed with premature oocyte depletion, and I believe that the use of the diagnosis POI leaves the door open for the occurrence of reproductive function and for the 5 to 10% of 46,XX patients who may spontaneously become pregnant. However, the world literature reports only two women with Turner syndrome, hypergonadotropic amenorrhea, and streak ovaries who have ever become pregnant spontaneously after their diagnosis. It would be unfair to such women with Turner syndrome to give them the same hope for pregnancy as we do for women with 46,XX POI. Amenorrheic women with Turner syndrome truly have ovarian failure. Although I have adopted the term POI in this article for women with Turner syndrome, semantics are no substitute for honest, thorough, and compassionate counseling.

Animal models for aberrations of gonadotropin action

During the last two decades a large number of genetically modified mouse lines with altered gonadotropin action have been generated. These mouse lines fall into three categories: the lack-of-function mice, gain-of-function mice, and the mice generated by breeding the abovementioned lines with other disease model lines. The mouse strains lacking gonadotropin action have elucidated the necessity of the pituitary hormones in pubertal development and function of gonads, and revealed the processes from the original genetic defect to the pathological phenotype such as hypo- or hypergonadotropic hypogonadism. Conversely, the strains of the second group depict consequences of chronic gonadotropin action. The lines vary from those expressing constitutively active receptors and those secreting follicle-stimulating hormone (FSH) with slowly increasing amounts to those producing human choriogonadotropin (hCG), amount of which corresponds to 2000-fold luteinizing hormone (LH)/hCG biological activity. Accordingly, the phenotypes diverge from mild anomalies and enhanced fertility to disrupted gametogenesis, but eventually chronic, enhanced and non-pulsatile action of both FSH and LH leads to female and male infertility and/or hyper- and neoplasias in most of the gonadotropin gain-of-function mice. Elevated gonadotropin levels also alter the function of several extra-gonadal tissues either directly or indirectly via increased sex steroid production. These effects include promotion of tumorigenesis in tissues such as the pituitary, mammary and adrenal glands. Finally, the crossbreedings of the current mouse strains with other disease models are likely to uncover the contribution of gonadotropins in novel biological systems, as exemplified by the recent crossbreed of LHCG receptor deficient mice with Alzheimer disease mice.

Retrospective Multicenter Study on Clinical Aspects in Premature Ovarian Failure

Objectives: Premature ovarian failure (POF) is a syndrome defined as the cessation of ovarian function before the age of 40 years that is characterized by amenorrhoea associated with elevated gonadotropin levels. The aim of this study was to compare clinical manifestation of primary amenorrhea and secondary amenorrhea group. Methods: This study was designed as a retrospective multicenter study of 262 women with premature ovarian failure. Sixty eight women with primary amenorrhea and 194 women with secondary amenorrhea were evaluated and hormonal level, lipid profile, bone mineral density, and pregnancy rates were compared. Results: The estradiol level was markedly lower in primary amenorrhea than secondary amenorrhea. The pregnancy rate of 43.3% before the diagnosis in secondary amenorrhea was markedly higher than the rate of 0% in primary amenorrhea. The pregnancy rates after treatment was 5.9% in primary amenorrhea, but 1.0% after diagnosis and 2.8% after treatment in secondary amenorrhea. The pregnancy rate after hormonal treatment was 3.7% in total, 8.3% in primary amenorrhea, and 2.8% in secondary amenorrhea. In nine cases of pregnancy, seven cases were after estrogen-progestin (EP), one case was after clomiphene citrate and one case was after EP/human menopausal gonodotropin (hMG). And In nine cases of pregnancy, six cases resulted from oocyte donation. The prevalence of osteopenia/osteoporosis was markedly higher in primary amenorrhea than in secondary amenorrhea. Conclusion: Premature ovarian failure has negative influences on the physical and psychological health of young patients. Effective management should include earlier diagnosis and intensive medical intervention to relieve symptoms of estrogen deficiency and to treat long-term disease such as osteoporosis and in assisted pregnancy by oocyte donation. (J Korean Soc Menopause 2011;17:160-165)

Male Hypogonadism: Childhood Diagnosis and Future Therapies

Male hypogonadism results from inadequate testicular function manifested by the impairment of both testosterone secretion and spermatogenesis. Hypogonadism has several etiologies. Hypogonadotropic hypogonadism (HH) results from hypothalamic–pituitary disorders leading to a complete or partial deficiency in gonadotropin-releasing hormone (GnRH) secretion from hypothalamic neurons, or gonadotropin secretion from anterior pituitary, or defects in GnRH receptor at the pituitary. All situations result in low or normal serum gonadotropin levels and low serum testosterone levels. Congenital HH can occur isolated (idiopathic HH) or in association with olfactory dysfunction (Kallmann’s syndrome). Gonadotropin deficiency can also occur with other pituitary hormone deficiencies. Most of the congenital isolated HH are still idiopathic. However, defects in more than ten genetic loci with multiple modes of inheritance, accounting for monogenic and occasionally oligogenic presentations were found in approximately 30% of cases. Acquired HH results from a hypothalamic–pituitary structural lesion as well as from tumors, trauma, autoimmunity or radiation. Hypergonadotropic hypogonadism is characterized by elevated serum gonadotropin levels due to testicular disorders, chromosomal abnormalities (Klinefelter syndrome), genetic syndromes as well as acquired conditions (autoimmunity, chemotherapy or radiation therapy). The main clinical feature of a male infant with hypogonadism is micropenis associated with or without cryptorchidism. The diagnosis of HH at childhood is difficult and usually postponed until adult age. At pubertal age, the differential diagnosis between the constitutional delay of growth and puberty, and HH is tricky and no hormonal test can consistently distinguish between these two disorders with 100% sensitivity and specificity; therefore, clinical follow-up is essential. Optimal management of male hypogonadism depends of the underlying etiology. Genetic tests are now available to detect genetic mutations in candidate genes essential for hypothalamic–pituitary axis function. Infants with micropenis require testosterone or dihydrotestosterone therapy to increase penile length. The first-line therapy for cryptorchidism is orchiopexy. Puberty should be induced with a low dose of testosterone and fertility could be achieved with chorionic gonadotropin hormone, recombinant luteinizing hormone and follicle stimulating hormone preparations or pulsatile GnRH injection. A small subset of HH patients may have a reversible phenotype enabling the withdrawal of medication in up to 10% of cases.

Plasma levels of kisspeptins in postmenopausal Chinese women do not show substantial elevation

The menopause, defined as the permanent cessation of menstruation resulting from ovarian failure, is characterized by elevated levels of serum gonadotropins. Recent studies have demonstrated that the gonadotropin hypersecretion in postmenopausal women is secondary to increase of KiSS-1 mRNA from the hypothalamus neurons, which encoded kisspeptin peptides. The present study was designed to determine whether plasma kisspeptins levels are altered in postmenopausal women. Blood samples were taken from 145 postmenopausal women, 35 young women and 30 pregnant women control in the first trimester. The plasma concentration of kisspeptins, follicle-stimulating hormone (FSH), luteinizing hormone (LH) and estradiol (E 2) was measured using immunoassay kits. Results indicated that plasma kisspeptins levels in postmenopausal women had higher than those in young women (5.25 ± 0.36; 4.48 ± 0.34 pmol/L), but no significant difference was found between the two groups ( p = 0.179). Plasma FSH and LH levels were significantly higher in postmenopausal women (124.67 ± 12.78, 57.14 ± 3.57 mIu/mL) than those in young women (9.23 ± 2.78, 7.56 ± 2.71 mIu/mL, p < 0.001). However, Plasma kisspeptins levels were not significantly correlated to FSH and LH in postmenopausal women ( r = −0.23, 0.324; p = 0.927, 0.176, respectively), and also there was no any correlation between plasma kisspeptins and E 2 in postmenopausal women ( r = −0.065; p = 0.792). Collectively, there was no significant difference in plasma kisspeptins levels between postmenopausal and young women. Our result suggested that kisspeptins’ role during menopause might mainly act in central rather than peripheral system and it could not be currently used as a clinical marker for menopause.

Premature ovarian failure

Premature ovarian failure (POF) is a common cause of infertility in women, and is characterised by amenorrhoea, hypo-oestrogenism and elevated gonadotrophin levels in women under the age of 40. Known causes include iatrogenic agents that cause permanent damage to the ovaries, such as chemotherapy, radiation therapy and surgery, autoimmune conditions, X-chromosome abnormalities and autosomal genetic conditions. However, few genes have been identified that can explain a substantial proportion of cases of POF. Most women with POF are deeply upset by the diagnosis, partly due to the unexpected menopausal symptoms, but also due to infertility. Therefore, early detection would provide better opportunity for early intervention, and furthermore, the identification of specific gene defects will help to direct potential targets for future treatment.