Increase In Gonadotropin Levels Research Articles

Divergent androgenic modulation of SARS-CoV-2 infection cooperates with dysregulated immune response to dictate worse COVID-19 outcomes in men

BackgroundSex-determined differences are rarely addressed in the management of diseases, despite well-known contrasting outcomes between female and male patients. In COVID-19 there is a remarkable disparity, with higher rates of mortality and more severe acute disease in men compared to women, who are mostly affected by long COVID-19. Furthermore, whether androgens play a protective or detrimental role in COVID-19 is still a matter of debate. Hence, the adequate management of the disease, especially regarding men presenting acute disease aggravation, still needs important data to elucidate the interplay between sex hormones and host immune responses that drive the worse evolution in male patients. MethodsA cohort of 92 controls and 198 non-severe and severe COVID-19 patients, from both sexes, was assessed for clinical outcomes, plasma steroids, gonadotropins, sex hormone binding globulin (SHBG) and immune mediators, before vaccination. These data were correlated with the global gene expression of blood leukocytes. The androgen receptor (AR) signaling pathway was investigated by transcriptomics and tracheal aspirate was obtained from severe patients for SARS-COV-2 quantification in the respiratory tract. The interplay among clinical, endocrine and immunological data deciphered the sex differences in COVID-19. Importantly, statistical analyses, using 95% confidence interval, considered confounding factors such as age and comorbidities, to definitely parse the role of androgens in the disease outcome. ResultsThere were notable contrasting levels of testosterone and dihydrotestosterone (DHT) throughout the disease course in male but not female patients. Inflammatory mediators presented significant negative correlations with testosterone, which was partially dependent on age and diabetes in men. Male subjects with severe COVID-19 had a significant up regulation of the AR signaling pathway, including modulation of TMPRSS2 and SRD5A1 genes, which are related to the viral infection and DHT production. Indeed, men had a higher viral load in the tracheal aspirate and levels of DHT were associated with increased relative risk of death. In contrast, the testosterone hormone, which was notably reduced in severe disease, was significantly related with susceptibility to COVID-19 worsening in male patients. Secondary hypogonadism was ruled out in the male severe COVID-19 subjects, as FSH, LH, and SHBG levels were not significantly altered. Instead, these subjects tended to have increased gonadotropin levels. Most interestingly, in this study we identified, for the first time, combined sets of clinical and immunoendocrine parameters that together predicted progression from non-severe to severe COVID-19 in men. One of the limitations of our study was the low or undetectable levels of DHT in many patients. Then, the evaluation of enzymes related to biosynthesis and signaling by androgens was mandatory and reiterated our findings. ConclusionsThese original results unraveled the disease immunoendocrine regulation, despite vaccination or comorbidities and pointed to the fundamental divergent role of the androgens testosterone and DHT in the determination of COVID-19 outcomes in men. Therefore, sex-specific management of the dysregulated responses, treatments or public health measures should be considered for the control of COVID-19 pandemic.

Cessation of chronic delta-9-tetrahydrocannabinol use partially reverses impacts on male fertility and the sperm epigenome in rhesus macaques

To determine whether discontinuation of delta-9-tetrahydrocannabinol (THC) use mitigates THC-associated changes in male reproductive health using a rhesus macaque model of daily THC edible consumption. Research animal study. Research institute environment. Adult male rhesus macaques (age, 8-10 years; n = 6). Chronic daily THC edible administration at medically and recreationally relevant contemporary doses followed by cessation of THC use. Testicular volume, serum male hormones, semen parameters, sperm deoxyribonucleic acid (DNA) fragmentation, seminal fluid proteomics, and whole genome bisulfite sequencing of sperm DNA. Chronic THC use resulted in significant testicular atrophy, increased gonadotropin levels, decreased serum sex steroid levels, changes in seminal fluid proteome, and increased DNA fragmentation with partial recovery after discontinuation of THC use. For every increase of 1 mg/7 kg/day in THC dosing, there was a significant decrease in the total testicular volume bilaterally by 12.6 cm3 (95% confidence interval [CI], 10.6-14.5), resulting in a 59% decrease in volume. With THC abstinence, the total testicular volume increased to 73% of its original volume. Similarly, with THC exposure, there were significant decreases in the mean total testosterone and estradiol levels and a significant increase in the follicle-stimulating hormone level. With increasing THC dose, there was a significant decrease in the liquid semen ejaculate volume and weight of coagulum; however, no other significant changes in the other semen parameters were noted. After discontinuing THC use, there was a significant increase in the total serum testosterone level by 1.3 ng/mL (95% CI, 0.1-2.4) and estradiol level by 2.9 pg/mL (95% CI, 0.4-5.4), and the follicle-stimulating hormone level significantly decreased by 0.06 ng/mL (95% CI, 0.01-0.11). Seminal fluid proteome analysis revealed differential expression of proteins enriched for processes related to cellular secretion, immune response, and fibrinolysis. Whole genome bisulfite sequencing identified 23,558 CpGs differentially methylated in heavy-THC vs. pre-THC sperm, with partial restoration of methylation after discontinuation of THC use. Genes associated with altered differentially methylated regions were enriched for those involved in the development and function of the nervous system. This is the first study demonstrating that discontinuation of chronic THC use in rhesus macaques partially restores adverse impacts to male reproductive health, THC-associated sperm differentially methylated regions in genes important for development, and expression of proteins important for male fertility.

Temporal decline of sperm concentration: role of endocrine disruptors.

Male infertility is a widespread disease with an etiology that is not always clear. A number of studies have reported a decrease in sperm production in the last forty years. Although the reasons are still undefined, the change in environmental conditions and the higher exposure to endocrine-disrupting chemicals (EDCs), namely bisphenol A, phthalates, polychlorinated biphenyls, polybrominated diphenyl esters, dichlorodiphenyl-dichloroethylene, pesticides, and herbicides, organophosphates, and heavy metals, starting from prenatal life may represent a possible factor justifying the temporal decline in sperm count. The aim of this study is to provide a comprehensive description of the effects of the exposure to EDCs on testicular development, spermatogenesis, the prevalence of malformations of the male genital tract (cryptorchidism, testicular dysgenesis, and hypospadias), testicular tumor, and the mechanisms of testicular EDC-mediated damage. Animal studies confirm the deleterious impact of EDCs on the male reproductive apparatus. EDCs can compromise male fertility by binding to hormone receptors, dysregulating the expression of receptors, disrupting steroidogenesis and hormonal metabolism, and altering the epigenetic mechanisms. In humans, exposure to EDCs has been associated with poor semen quality, increased sperm DNA fragmentation, increased gonadotropin levels, a slightly increased risk of structural abnormalities of the genital apparatus, such as cryptorchidism and hypospadias, and development of testicular tumor. Finally, maternal exposure to EDCs seems to predispose to the risk of developing testicular tumors. EDCs negatively impact the testicular function, as suggested by evidence in both experimental animals and humans. A prenatal and postnatal increase to EDC exposure compared to the past may likely represent one of the factors leading to the temporal decline in sperm counts.

Methanol Extract of Azanza garckeana Fruit Pulps Protects against Formalin-Induced Reproductive Toxicity in Adult Albino Male Mice

Introduction: The aqueous extract of Azanza garckeana was recently reported of exhibiting ameliorative and pro-fertility properties however the protective effects on formalin testicular toxicity have not been studied.
 Objective: This study investigated the protective effect of methanol extract of Azanza garckeana on formalin-induced testicular toxicity.
 Methods: Forty male albino mice were randomly divided into 8 groups of 5. Animals in the first group (1) served as control and administered normal saline (1 ml/kg) by the oral route daily for 40 days. In similar manner, animal in groups 2 received formalin (10 mg/kg) by the IP route, while animals in groups 3; 4 and 5 concurrently received formalin (10 mg/kg IP) and extract at doses of 125; 250 and 500 mg/kg respectively by the oral route. Mice in groups 6; 7 and 8 received the extract at doses of 125; 250 and 500 mg/kg respectively. Phytochemical analysis was conducted for each constituent using specific methods. Gonadotropin and sperm analysis were carried out using standard methods.
 Result: Phytochemical screening revealed the presence of various constituents, but notably flavonoids. Induced-toxicity with formalin and concurrent treatment with extract at doses of 250 and 500 mg/kg from day 20 to 40 caused significant body weight increase compared to baseline (p < 0.05). Similarly, treatment with the extract alone at all doses caused significant increase in body weight from day 20 to 40 (p < 0.05). Treatment with the extract at 250 and 500 mg/kg, caused a significant increase in weight of testes and epididymis compared to control and untreated group (p < 0.05).The extract induced significant increase in gonadotropin levels of animals compared to control and the untreated group (p < 0.05).The extract at 125 mg/kg demonstrated the highest fecundity potential, but there was no any consistent relationship between GSI and fecundity.
 Conclusion: This investigation was able to establish the protective and pro-fertility potentials of methanol extract of Azanza garckeana.

Hypothalamic-pituitary-gonadal axis and sexual functioning in metformin-treated men after discontinuation of testosterone replacement therapy: A pilot study.

Metformin was found to reduce elevated gonadotropin levels. The aim of the present study was to determine whether metformin modulates the impact of discontinuation of testosterone therapy on hypothalamic-pituitary-gonadal axis activity and sexual function in men with low testosterone levels. The study included 28men with late-onset hypogonadism (defined according to the criteria of the European Male Aging Study group) receiving testosterone undecanoate (120mg in three equal doses), 12 of whom had been treated with oral metformin (1.7-3g daily). Both testosterone and metformin had been administered for at least six months before enrolment. In all patients, testosterone replacement required to be discontinued. The control group included 16 testosterone- and metformin-treated men with late-onset hypogonadism who during the entire study period continued their treatment. Glucose homeostasis markers, as well as plasma levels of insulin, gonadotropins, testosterone, calculated bioavailable testosterone, dehydroepiandrosterone-sulphate, oestradiol, thyrotropin, free thyroxine, prolactin, insulin-growth factor-1 and cortisol were measured at the beginning of the study and four months later. Moreover, at the beginning and the end of the study, all enrolled patients completed a questionnaire assessing their sexual functioning (IIEF-15). Discontinuation of testosterone therapy resulted in a decrease in total testosterone and bioavailable testosterone (by 42% and 45% in metformin-treated patients, and by 52% and 54% in metformin-naïve patients), as well as impaired all aspects of male sexual function. Changes in bioavailable testosterone, as well as in erectile function, orgasmic function and sexual desire were less pronounced if subjects received metformin. Only in metformin-naïve men, follow-up FSH and LH levels were higher than at baseline (by 75% and 62%). Moreover, discontinuation of testosterone therapy in metformin-naïve men increased glycated haemoglobin, as well as worsened insulin sensitivity. There were no differences between baseline and follow-up levels of the remaining hormones. In metformin-naïve subjects, the increase in gonadotropin levels correlated with the changes in testosterone levels and insulin sensitivity. No effect on glucose homeostasis markers, hormone levels and sexual functioning was observed in the control group. The obtained results suggest that metformin treatment mitigates the unfavourable effect of discontinuation of testosterone treatment on hypothalamic-pituitary-testicular axis activity and sexual function in men with late-onset hypogonadism.

Long-Term Risk of Ovarian Cancer and Borderline Tumors After Assisted Reproductive Technology

(Abstracted from J Natl Cancer Inst 2021;113:699–709) Despite inconclusive evidence, concerns that assisted reproductive technology may be associated with increased risk of ovarian cancer remain. Significant increases in gonadotropin levels and disruption of ovarian epithelium have been proposed as mechanisms to explain this potential association.

Efficacy and safety of pulsatile gonadotropin-releasing hormone therapy in patients with congenital hypogonadotropic hypogonadism: a multicentre clinical study.

BackgroundPulsatile gonadotropin-releasing hormone (GnRH) therapy may restore function of the hypothalamus-pituitary-gonad axis and induce spermatogenesis in male patients with congenital hypogonadotropic hypogonadism (CHH). The study sought to test the reliability of a newly developed Innopump® hormone pump, and to confirm the efficacy and safety of pulsatile GnRH therapy (by Innopump® hormone pump) in CHH patients.MethodsFrom November 2017 to November 2018, 28 male patients with CHH were treated with pulsatile GnRH at Peking Union Medical College Hospital, Beijing Chaoyang Hospital, and Shandong Provincial Hospital. A prospective, self-controlled, 7-day clinical trial was conducted. The primary outcome measures were the efficacy and safety of pulsatile GnRH therapy (which was administered via the Innopump® hormone pump). The secondary outcome measures included total serum testosterone, luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels.ResultsAll of the patients participated the clinical study. For 7 days, a dosage prescribed by doctors was accurately administered by the Innopump® hormone pump, and recorded by the pump. During the treatment, LH and FSH levels gradually increased to 2.66±1.74 and 5.05±3.03 IU/L, respectively. Upper respiratory tract infection in 1 patient and slight nausea in another patient were reported, which were confirmed to be unrelated to the pulsatile GnRH therapy.ConclusionsThe Innopump® hormone pump was found to be reliable in drug administration, and to have an accurate alarming system. It effectively and safely treated patients with CHH. Pulsatile GnRH therapy may produce a physiological pattern of GnRH secretion, and re-establish pituitary-gonad axis function by increasing gonadotropin levels.

Peculiarities of hormonal homeostasis in perimenopausal and postmenopausal women with menopausal disorders

According to WHO, now on the planet 46% of women are over the age of 45 years, among women in Ukraine – this is almost half (13.2 million). Of these, 46-68% suffer from climacteric syndrome. An increase in the duration of a healthy life and prolongation of the age of working capacity acquire not only medical, but also socio-economic significance, both in Ukraine and in other European countries. Therefore, the aim of the study was a comprehensive (involving pituitary, ovarian, adrenal and thyroid hormones) hormonal examination of women of peri- and postmenopausal age with menopause syndrome to identify the most likely hormonal predictors of this pathology. For this purpose, 64 women of perimenopausal and postmenopausal age with menopause and 42 healthy women of the same age categories had a study of the concentration of pituitary (LH, FSH, prolactin), ovarian hormones (estradiol, progesterone, testosterone), thyroid hormones (TSH, triiodothyronine (T3), thyroxine (T4)) and adrenal glands (DHEA-s, cortisol) in blood plasma. Hormones were determined using a set of test systems from “Immunotech” (Czech Republic-France) using the radio-immune method. Comparisons of the quantitative data of the two related groups (before and after treatment) were made using Wilcoxon signed rank test. When differences were detected, pairwise group comparisons were performed using the Mann-Whitney test. In women of perimenopausal and postmenopausal age with menopause syndrome, compared with healthy women of the same age groups, a significant increase in gonadotropin levels (LH by 3.7 and 3.0 times, respectively; FSH by 1.6 and 1.9 times) and a decrease indicator of prolactin in 1.5 and 1.2 times; estradiol 1.2 and 2.2 times and testosterone 2.9 and 2.4 times. A significant decrease in progesterone by 1.9 times occurred only in the group of postmenopausal women with menopause syndrome. In women of perimenopausal and postmenopausal age of the main group, a significant decrease was found in comparison with the control of DHEA-s levels by 1.3 times and 2.2 times, respectively; cortisol 1.2 and 2.0 times; TSH is 2.6 times and 2.0 times, respectively, however, thyroxine tended to increase (the probability p<0.05 was valid only for women of perimenopausal age). Thus, in postmenopausal women with menopausal syndrome, hormonal imbalance is more pronounced, indicating a deep atrophy of hormone-dependent tissue receptors and, as a result, a deepening of involutive processes.

MON-235 Bone Morphogenic Protein Receptor Variants: A New Cause of Primary Ovarian Insufficiency

Primary ovarian insufficiency (POI) is a major cause of infertility. This disease is characterized by amenorrhea with an increase in gonadotropin levels and affects 1% of women before the age of 40. POI may be the result of a broad spectrum of disorders caused by two main mechanisms: abnormal follicular development and follicle depletion due to a defect in their formation or an aberrantly rapid depletion of the stock. Although the majority of cases are idiopathic, POI can be trigged by autoimmune disease, infectious agents, iatrogenic effects, or genetic causes. It may also be part of syndromic diseases such as Turner, Fragile-X or Blepharophimosis Ptosis Epicanthus Inversus syndrome. However, in the majority of cases, the cause of POI is unknown suggesting that new causative genes are yet to be discovered. We conducted a Whole Exome Sequencing on 69 Caucasian women with sporadic POI and performed a bioinformatics analysis on a specific subset of 420 coherent candidate genes1. We identified variations in about fifty genes potentially linked to POI, including new genes never described to be associated with the diseases aetiology, such as AuTophagy related Genes (ATG)2, KHDRBS1 gene encoding an RNA-binding protein3, NOTCH2 gene4... We also found variants in genes encoding Bone Morphogenetic Protein Receptors (BMPR1A and BMPR1B) in three patients. These receptors bind ligands of TGFβ superfamily. Mutations of members of this family (e.g. BMP15, GDF9) are known to be involved in the etiology of POI. BMPR encode transmembrane receptors with serine-threonine kinase activity expressed in the granulosa cells of growing follicles. Missense variations, located in the kinase domain of both receptors 1A and 1B, are predicted to be deleterious in silico. We studied the signaling pathway of these receptors: SMAD proteins phosphorylation, measurement of their transcriptional activity and expression of specific target genes and showed that they are deleterious. Bmpr1a -/- and Bmpr1b-/- mouse models develop infertility due to a reduced spontaneous ovulation and compromised cumulus expansion respectively, indicating that both genes play a crucial role in fertility. Altogether, our study describes the first BMPR1A and 1B mutations associated with POI and increases the number of genes formally implicated as being responsible for this condition. 1Patiño LC, Beau I, Carlosama C, Buitrago JC, González R, Suárez CF, Patarroyo MA, Delemer B, Young J, Binart N, Laissue P. Hum Reprod. 2017; 32(7):1512-1520. 2Delcour C, Amazit L, Patino L, Magnin F, Fagart J, Delemer B, Young J, Laissue P, Binart N, Beau I. Genet Med. 2018 (in press) 3Carlosama C, Patiño L, Beau I, Morel A, Delemer B, Young J, Binart N, Laissue P. Clin Endocrinol (Oxf). 2018 (in press) 4Patiño LC, Beau I, Morel A, Delemer B, Young J, Binart N, Laissue P. Hum Mutat. 2018 (in press)

Two rare loss-of-function variants in the STAG3 gene leading to primary ovarian insufficiency

Background/AimPrimary ovarian insufficiency (POI) is characterized by primary or secondary amenorrhea, infertility, low estradiol levels, and increased gonadotropin levels. Most cases of POI remain unsolved even after exhaustive investigation. Here, we performed a targeted massively parallel sequencing to identify the genetic diagnosis of primary ovarian insufficiency (POI) in a Brazilian patient. Patient and methodsAn adopted 21-year-old Brazilian woman with isolated POI was selected. A custom SureSelectXT DNA target enrichment panel was designed and sequenced on an Illumina NextSeq 500 sequencer. The variants were confirmed using Sanger sequencing. ResultsTwo rare heterozygous pathogenic variants in the STAG3 gene were identified in our patient. An unpublished 1-bp duplication c.291dupC (p.Asn98Glnfs*2) and one stop codon variant c.1950C > A (p.Tyr650*) were identified in the STAG3 gene. Both undescribed heterozygous variants were absent in the public databases [1000Genomes, Exome Aggregation Consortium (ExAC), National Heart, Lung, and Blood Institute Exome Variant Server (NHLBI/EVS), database of Single Nucleotide Polymorphisms (dbSNP), Genome Aggregation Database (gnomAD)], and Online Archive of Brazilian Mutations (ABraOM) databases. Moreover, neither heterozygous variants were found in 400 alleles from fertile Brazilian women screened by Sanger sequencing. The parents' DNA was not available to segregate these variants. ConclusionOur results suggested that POI is caused by pathogenic compound heterozygous variants in the STAG3 gene, supporting the key role of the STAG3 gene in the etiology of primary ovarian insufficiency.

A Novel Homozygous Missense FSHR Variant Associated with Hypergonadotropic Hypogonadism in Two Siblings from a Brazilian Family

Hypergonadotropic hypogonadism (HH) is defined by increased gonadotropin levels in men and women. Primary ovarian failure (POF) is a form of female infertility characterized by amenorrhea, hypoestrogenism, and elevated gonadotropin levels in women under the age of 40 years. Although several genes have been associated with POF, its causative genes remain to be identified. Here, we used whole-exome sequencing (WES) to study a consanguineous family with a 46,XX girl and a 46,XY man affected by HH. All exons of both siblings and their parents were captured and massively sequenced by WES, and the candidate variant was confirmed by Sanger sequencing. A novel c.1298C>A;p.Ala433Asp missense variant of the follicle-stimulating hormone receptor (FSHR) gene was found in both affected siblings in a homozygous state and in their parents in a heterozygous state. This FSHR variant is not present in available databases (1000 Genomes and NHLBI/EVS) and Brazilian exome controls. Moreover, it is highly conserved and predicted as deleterious in all prediction sites analyzed. In conclusion, the novel homozygous FSHR variant observed in 2 siblings with HH can expand the spectrum of FSHR mutations in humans.

Lack of Rev7 function results in development of tubulostromal adenomas in mouse ovary

Rev7 is a subunit of Polζ, one of the translesion DNA synthesis (TLS) polymerases involved in DNA damage repair. We recently found that Rev7 is also essential for germ cell development in mouse. In the present study, we found the development of ovarian tumors in Rev7 mutant mouse, suggesting the involvement of TLS deficiency in the etiology of ovarian tumor. The Rev7 mutant mice showed complete lack of oocytes and follicles in the ovary. The lack of follicles causes a significant increase of gonadotropin level and an increase in the proliferation of ovarian cells. As a result, the weight of the ovaries of Rev7 mutant mice increased with age and they developed tubulostromal adenomas. However, the remarkable overgrowth of ovaries occurred after gonadotropin level decreases at older ages, suggesting gonadotropin-independent progression of the ovarian tumors. In addition, the Rev7 mutant fibroblasts and ovarian cells showed significant accumulation of DNA damage. These findings suggest that not only increased gonadotropin levels but also lack of DNA damage repair function could be responsible for the development of ovarian tumors in the Rev7 mutant mouse.

The Effect of Aggressive Rosuvastatin Treatment on Steroid Hormone Production in Men with Coronary Artery Disease

Most steroid hormones are produced from cholesterol contained in low-density lipoproteins, which is uptaken by the gonads and adrenal cortex, and used as a substrate for steroidogenesis. Theoretically, in states associated with very low-density lipoprotein (LDL) cholesterol levels, cholesterol conversion to steroid hormones may be impaired. The study included 15 men with coronary artery disease, in whom initial statin treatment had been unsuccessful and therefore was replaced with rosuvastatin (20-40mg daily). Although in 11 patients, rosuvastatin decreased plasma LDL cholesterol levels to below 70mg/dL, the drug only moderately reduced testosterone levels and increased gonadotropin levels, as well as insignificantly increased plasma ACTH levels. Aggressive rosuvastatin treatment did not affect plasma cortisol and dehydroepiandrosterone sulphate levels, and urine free cortisol. Our results suggest that intensive rosuvastatin treatment is associated with only small changes in adrenal and testicular steroidogenesis.

Low Serum Concentrations of Anti-Müllerian Hormone Are Common in 53 Female Childhood Cancer Survivors

Background/Aims: Gonadal dysfunction is one of the major endocrinological late effects among childhood cancer survivors (CCSs). Periodic screening evaluation of gonadotropins and sex steroids has been recommended, although it remains difficult to predict gonadal function and reproductive capacity in childhood. We evaluated the effects of cancer treatments on the ovarian function of Japanese female CCSs by measuring serum levels of anti-Müllerian hormone (AMH) and gonadotropin. Methods: This was a retrospective, cross-sectional study at a single hospital. Results: Among 53 female CCSs, 28 (53%) had a decreased AMH level, while only 16 (30%) had an increased follicle-stimulating hormone (FSH) level. AMH was low in all patients with high FSH, while FSH was not elevated in 43% of patients with a low AMH level. AMH was low in 8 of 9 patients with no breast development, 11 of 14 patients with no spontaneous menstruation, and 3 of 22 patients with regular menstrual cycles. Conclusion: Measurement of AMH concentration is useful as a marker of ovarian reserve in female CCSs for detecting primary gonadal deficiency, particularly among patients without increased gonadotropin levels.

Bilateral Undescended Testes Classified According to Preoperative and Postoperative Status of Gonadotropins and Inhibin B in Relation to Testicular Histopathology at Bilateral Orchiopexy in Infant Boys

In recent series of boys with cryptorchidism gonadotropin levels have been higher and serum inhibin B levels have been lower than normal. To some extent the serum values of inhibin B reflect the state of germinative epithelium in cryptorchid testes. We evaluated whether blood samples of gonadotropins and inhibin B as well as histopathology could be used to classify undescended testes. A total of 69 boys (median age 2 years) who underwent surgery for bilateral cryptorchidism had blood samples taken preoperatively and 3 months to 2.1 years postoperatively. Testicular biopsies were performed bilaterally at orchiopexy. The average germ cell number per tubular transverse tubule was measured. Group 1 included 17 patients with increased follicle-stimulating hormone levels. Serum follicle-stimulating hormone and luteinizing hormone decreased significantly after surgery. In 77% of patients (13 of 17) follicle-stimulating hormone levels were normalized. Of these boys 35% (6 of 17) had a low postoperative serum inhibin B. Group 2 consisted of 27 patients with a decreased germ cell number and/or low preoperative inhibin B, but not increased serum follicle-stimulating hormone or luteinizing hormone. There were no significant postoperative changes in follicle-stimulating hormone and luteinizing hormone. Of these boys 22% (6 of 27) had a low serum inhibin B postoperatively. In group 3 there were 25 patients with a normal germ cell number, normal preoperative serum inhibin B and normal gonadotropins. There were no significant changes in luteinizing hormone and follicle-stimulating hormone postoperatively. Only 1 boy in this group had a low postoperative serum inhibin B. Patients with increased gonadotropin levels may have testicular dysgenesis and some may benefit from early surgery. Patients with normal gonadotropin levels and a decreased germ cell number have transient hypothalamus-pituitary-gonadal hypofunction and a poor fertility prognosis. These patients may benefit from gonadotropin treatment after orchiopexy. Patients with normal gonadotropins, inhibin B and germ cell number have a good fertility prognosis after surgery.

Bone loss in premenopausal, perimenopausal and postmenopausal women: results of a prospective observational study over 9 years

ABSTRACTIntroduction Few longitudinal data about rates of bone loss in women in midlife exist. Fewer still with their reproductive states having been carefully assessed and sequentially followed-up.Methods Complete data from 50 women younger than 60 years (mean age at baseline 48.3±5.4 years) were prospectively collected over 9 years. This was done by standardized interviews, measurement of endocrinological parameters as well as bone markers and repeated bone mineral density (BMD) measurements using quantitative computer tomography (QCT). Women were classified in three groups according to their reproductive characteristics over 9 years.Results Significant BMD loss was found in women going through the menopausal transition. In perimenopause, there was a correlation (multiple regression results, r = −0.396 and r = −0.527) between accelerated bone density loss and increased gonadotropin levels (follicle stimulating hormone, luteinizing hormone). Although significantly higher levels of bone markers (osteocalcin, bone-specific alkaline phosphatase, c-terminal telopeptide cross-linked collagen type I) were measured in postmenopause, the greatest increase in these markers was seen during the menopausal transition. No individual marker's increase, however, was predictive for perimenopausal bone density loss. The major risk factors for rapid bone loss were a lower initial body weight (< 57 kg), a body mass index < 20 kg/m2 as well as a positive family history of fragility fractures.Conclusions Women in the menopausal transition lose trabecular bone at a rapid rate despite intermittently high and usually normal estrogen levels. This is the only prospective study to date that documents trabecular bone changes in women through the entire perimenopause, which may last up to 10 years.

Anti-Müllerian hormone: an ovarian reserve marker in primary ovarian insufficiency

Primary ovarian insufficiency (POI), also known as premature ovarian failure, is a disorder of infertility characterized by amenorrhoea, low estrogen levels and increased gonadotropin levels in women aged <40 years. POI is the result of premature exhaustion of the follicle pool or can be attributed to follicular dysfunction, for example, owing to mutations in the follicle-stimulating hormone receptor or steroidogenic cell autoimmunity. Moreover, advances in cancer therapeutics over the past decades have led to increasing survival rates for both paediatric and adult malignancies. Given the gonadotoxic effect of many cancer treatments, more women develop POI. A marker that predicts whether women are at risk of POI would, therefore, aid in early diagnosis and fertility counselling. Anti-Müllerian hormone (AMH), a growth factor produced solely by small, growing follicles in the ovary, might constitute such a marker, as serum levels of this hormone correlate strongly with the number of growing follicles. In addition, AMH could potentially help assess the progression of ovarian senescence, as serum AMH levels are independent of hypothalamic-pituitary-gonadal axis function and decrease to undetectable levels at menopause. In cancer survivors, serum AMH levels correlate with the extent of gonadal damage. In this Review, we provide an overview of the current studies that have measured AMH in women with POI of various aetiologies and discuss its possible application as a marker to determine ovarian reserve.

Evaluation of the relationship between endogenous gonadotropins and female sexual function and psychological status in predialysis and hemodialysis patients

Objectives: To evaluate sexual function and psychological state and the factors affecting female sexual dysfunction in predialysis and hemodialysis patients. Design and methods: Forty-seven women with chronic renal failure including 22 predialysis patients, 25 hemodialysis patients, and 30 healthy controls were included in this study. Demographic and clinical variables of the patients were recorded. The sexual functions and psychological states of the patients, assessed by the Arizona Sexual Experiences Scale (ASEX) and Beck Depression Inventory (BDI), respectively, were compared between the groups. Results: Total ASEX scores, ability to reach orgasm, and BDI scores were significantly higher in predialysis and hemodialysis patients than controls, reflecting sexual dysfunction. The patients in the predialysis group were 6 and 3.8 times more likely to develop depressive symptoms compared to the controls and hemodialysis patients, respectively. The predialysis patients who showed depressive symptoms were 24 times more likely to develop sexual dysfunction compared to those without depression. Serum FSH and LH levels were also positively correlated with arousal and erection/lubrication scores in the predialysis patients with depressive symptoms. Conclusion: Female predialysis rather than dialysis patients might be more likely to develop depression. Those patients with depressive symptoms may also be at greater risk of developing sexual dysfunction in which increased gonadotropin levels and age may also be contributing factors. Therefore, psychiatric and gynecologic consultations may be beneficial.

Induction of a menopausal state alters the growth and histology of ovarian tumors in a mouse model of ovarian cancer

Ovarian cancer is often diagnosed in women after menopause when the levels of the serum gonadotropins follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are increased because of the depletion of growing follicles within the ovary. The ability of FSH and LH to modulate the disease has not been well studied owing to a lack of physiologically relevant models of ovarian cancer. In this study, 4-vinylcyclohexene diepoxide (VCD) was used to deplete ovarian follicles and increase the levels of circulating FSH and LH in the tgCAG-LS-TAg mouse model of ovarian cancer. VCD-induced follicle depletion was performed either before or after induction of the oncogene SV40 large and small T-antigens in the ovarian surface epithelial cells of tgCAG-LS-TAg mice, which was mediated by the intrabursal delivery of an adenovirus expressing Cre recombinase (AdCre). tgCAG-LS-TAg mice injected with AdCre developed undifferentiated ovarian tumors with mixed epithelial and stromal components and some features of sex cord stromal tumors. Treatment with VCD before or after AdCre injection yielded tumors of similar histology, but with the unique appearance of Sertoli cell nests. In mice treated with VCD before the induction of tumorigenesis, the ovarian tumors tended to grow more slowly. The human ovarian cancer cell lines SKOV3 and OVCAR3 responded similarly to increased levels of gonadotropins in a second model of menopause, growing more slowly in ovariectomized mice compared with cycling controls. These results suggest that follicle depletion and increased gonadotropin levels can alter the histology and the rate of growth of ovarian tumors.

Microdose gonadotropin-releasing hormone agonist in the absence of exogenous gonadotropins is not sufficient to induce multiple follicle development

Because the effectiveness of the "microdose flare" stimulation protocol often is attributed to the dramatic endogenous gonadotropin release induced by the GnRH agonist, the aim of this study was to determine whether use of microdose GnRH agonist alone could induce multiple ovarian follicle development in normal responders. Based on these data, the duration of gonadotropin rise is approximately 24 to 48 hours and is too brief to sustain continued multiple follicle growth.