Reproductive Endocrine Function Research Articles

DDTs in Maternal Early Postpartum Serum Predicts Testosterone, FSH, and Semen Quality in Adult Sons: Evidence from the Child Health and Development Studies

DDTs in Maternal Early Postpartum Serum Predicts Testosterone, FSH, and Semen Quality in Adult Sons: Evidence from the Child Health and Development StudiesAbstract Number:2820 Barbara Cohn*, Piera Cirillo, Myrto Petreas, June-Soo Park, Sabrina Crispo Smith, Nickilou Krigbaum, and Pam Factor- Litvak Barbara Cohn* Public Health Institute, United States, E-mail Address: [email protected] Search for more papers by this author , Piera Cirillo Public Health Institute, United States Search for more papers by this author , Myrto Petreas California Environmental Protection Agency, United States Search for more papers by this author , June-Soo Park California Environmental Protection Agency, United States Search for more papers by this author , Sabrina Crispo Smith California Environmental Protection Agency, United States Search for more papers by this author , Nickilou Krigbaum Public Health Institute, United States Search for more papers by this author , and Pam Factor- Litvak Columbia University, United States, E-mail Address: [email protected] Search for more papers by this author AbstractIntroduction: DDT compounds are reproductive toxins in wildlife. We tested the hypothesis that perinatal exposure to the DDTs predict testosterone and FSH and are linked to sermen quality in adult males.Methods: In a sample of 195 adult men whose mothers were enrolled in Child Health and Development Studies in the 1960s, we measured p,p’-DDT, the primary ingredient of commercial DDT, o,p’-DDT, a lower concentration contaminant, and p,p’-DDE, the primary metabolite of p,p’-DDT in maternal serum collected 1-3 days after her son’s birth. We measured serum levels of testosterone and FSH and evaluated semen concentration, sperm motility, and sperm morphology when the sons were age 39 to 47. Linear regression controlling for potential confounders was used to estimate the associations of maternal serum DDTs with hormones, and semen parameters. Hormones and sperm concentration were positively skewed and so were natural log transformed.Results: A higher ratio of FSH to Testosterone (T) was a strong, consistent and significant predictor of lower sperm concentration, lower percent motility and lower percent normal morphology. In utero exposure to p,p’-DDT significantly predicted a higher ratio of FSH to T in adult males (p<0.03), consistent with the hypothesis that perinatal exposure to p,p’-DDT in utero disrupts reproductive endocrine function in males. There was evidence that faster conversion of p,p’-DDT to its metabolite p,p’- DDE, in response to recent exposure, was protective (p<0.01). Associations of perinatal p,p’-DDT with semen parameters were not statistically significant, but were consistent with lower semen quality (lower concentration, motility, and normal morphology) with higher perinatal p,p’-DDT exposure.Conclusion: Exposure to p,p’-DDT in utero appears to disrupt reproductive endocrine function in adult males.

Testicular Function, Semen Quality, and Fertility in Young Men After Renal Transplantation During Childhood or Adolescence.

Purpose. This study was conducted to assess reproductive endocrine function, testicular volume, semen quality, and fertility in adult male patients after renal transplantation (RTx) during childhood or adolescence. Methods. Twenty-four RTx recipients (median age: 28.1 years) were examined at a median of 18.6 years after RTx. Reproductive hormone levels and semen samples were studied and compared to those of 56 age-matched controls (median age: 30.2 years). Eighteen patients and 54 controls provided a semen sample. Eight RTx men (33%) had been treated with cyclophosphamide. Medical records were retrospectively reviewed and data on puberty, dialysis, and immunosuppressive medication were analyzed to evaluate the prospect of fertility. Results. The testicular volumes and total sperm counts of the RTx patients were smaller than those of the controls with a median of 11.4 ml vs. 33.9 ml, p<0.001 and 1.3 million vs. 135.5 million, p<0.001, respectively. Only 4 (22%) of the RTx men had normospermia in semen sample. Both the median testicular volumes and total sperm counts were further decreased in patients with a history of cyclophosphamide treatment (8.5 ml and 0 million, respectively) in comparison with their healthy peers (p<0.001 in both) and even worse than in the RTx patients without a history of cyclophosphamide treatment (12.5 ml, p<0.001 and 16.3 million, p<0.001, respectively). Neither the cumulative duration of dialysis nor the concurrent kidney graft function correlated significantly with the semen parameters. The median testosterone and calculated free testosterone levels of the RTx patients were lower than those of the controls (17.5 nmol/l vs. 18.5 nmol/l, p=0.048 and 322 pmol/l vs. 399 pmol/l, p=0.001, respectively) but the actual levels of the reproductive hormone levels were normal in the majority of the RTx patients with only two men showing androgen deficiency. Conclusions. Testicular function is often impaired even years after transplantation and poor semen quality decreases the prospect of fertility in men after pediatric RTx.

Allopregnanolone as a mediator of affective switching in reproductive mood disorders.

Reproductive mood disorders, including premenstrual dysphoria (PMD) and postpartum depression (PPD), are characterized by affective dysregulation that occurs during specific reproductive states. The occurrence of illness onset during changes in reproductive endocrine function has generated interest in the role of gonadal steroids in the pathophysiology of reproductive mood disorders, yet the mechanisms by which the changing hormone milieu triggers depression in susceptible women remain poorly understood. This review focuses on one of the neurosteroid metabolites of progesterone - allopregnanolone (ALLO) - that acutely regulates neuronal function and may mediate affective dysregulation that occurs concomitant with changes in reproductive endocrine function. We describe the role of the "neuroactive" steroids estradiol and progesterone in reproductive endocrine-related mood disorders to highlight the potential mechanisms by which ALLO might contribute to their pathophysiology. Finally, using existing data, we test the hypothesis that changes in ALLO levels may trigger affective dysregulation in susceptible women. Although there is no reliable evidence that basal ALLO levels distinguish those with PMD or PPD from those without, existing animal models suggest potential mechanisms by which specific reproductive states may unmask susceptibility to affective dysregulation. Consistent with these models, initially euthymic women with PMD and those with a history of PPD show a negative association between depressive symptoms and circulating ALLO levels following progesterone administration. Existing animal models and our own preliminary data suggest that ALLO may play an important role in the pathophysiology of reproductive mood disorders by triggering affective dysregulation in susceptible women.

Assessment of Reproductive Function in Southern African Spiny Mice (Acomys spinosissimus) using Faeces as Hormone Matrix

For spiny mice, detailed long-term data on reproductive endocrine function is lacking, as limited blood volumes make frequent collections of individual plasma samples for hormone monitoring impractical. To provide the necessary tools in order to fill this gap, this study examined the suitability of two enzyme immunoassays for monitoring male and female reproductive function in the southern African spiny mouse (Acomys spinosissimus) based on faecal hormone analysis. Fourteen non-pregnant and one pregnant female and 24 male spiny mice were wild-caught and subsequently monitored under controlled conditions. Thirteen of the 14 non-pregnant females revealed elevated faecal progestagen metabolite concentrations with eight individuals showing indications of a luteal phase. Two females showed two post-ovulatory luteal phases with estimated cycle lengths of 16 and 18 days, respectively. The pregnant female had an elevated (231%) mean faecal progestagen metabolite level compared with the overall mean baseline hormone concentration determined for the 14 non-pregnant females. Males exposed to a long photoperiod, simulating summer-related breeding activity, exhibited a 47.8% increase in faecal androgen metabolite levels compared with males exposed to a short photoperiod. Collectively, the data demonstrated that reproductive endocrine function can be monitored in male and female spiny mice by measuring respective faecal hormone metabolites.

Assessment of reproductive function in southern African spiny mice (Acomys spinosissimus) using faeces as hormone matrix

For spiny mice, detailed long-term data on reproductive endocrine function is lacking, as limited blood volumes make frequent collections of individual plasma samples for hormone monitoring impractical. To provide the necessary tools in order to fill this gap, this study examined the suitability of two enzyme immunoassays for monitoring male and female reproductive function in the southern African spiny mouse (Acomys spinosissimus) based on faecal hormone analysis. Fourteen non-pregnant and one pregnant female and 24 male spiny mice were wild-caught and subsequently monitored under controlled conditions. Thirteen of the 14 non-pregnant females revealed elevated faecal progestagen metabolite concentrations with eight individuals showing indications of a luteal phase. Two females showed two post-ovulatory luteal phases with estimated cycle lengths of 16 and 18 days, respectively. The pregnant female had an elevated (231%) mean faecal progestagen metabolite level compared with the overall mean baseline hormone concentration determined for the 14 non-pregnant females. Males exposed to a long photoperiod, simulating summer-related breeding activity, exhibited a 47.8% increase in faecal androgen metabolite levels compared with males exposed to a short photoperiod. Collectively, the data demonstrated that reproductive endocrine function can be monitored in male and female spiny mice by measuring respective faecal hormone metabolites.

Implications of 25-Year Follow-Up of White Matter Integrity and Neurocognitive Function of Childhood Leukemia Survivors: A Wake-Up Call

Improved treatment via new drug development, combination therapy, and methods of treatment have resulted in 73% to 80% of children treated for acute lymphoblastic leukemia (ALL) being considered long-term survivors who are cured. This survival rate has not come without a cost, with long-term consequences (late effects) occurring in reproductive capacity, cardiac function, neurocognitive function, endocrine function, pulmonary function, and second malignancy related to treatment. As children survive longer into adulthood, an additional late effect is beginning to be recognized: an onset of diseases associated with aging occurring earlier than in the general population. Though much is known about neurocognitive late effects in children and adolescents during school-age and adolescence, nothing is known about the long-term effects of treatment received during childhood on the survivors of ALL 20 to 30 years after diagnosis. In the article accompanying this editorial, Schuitema et al describe one of the first studies in this area, and the results are consistent with other late-effects studies related to early aging concerns. Ninety-three young adults treated between 1978 and 1990 for childhood ALL with either cranial radiation therapy (CRT) or CNS prophylaxis with chemotherapy were evaluated using magnetic resonance imaging (MRI) and standardized tests of neurocognitive function. Survivors who were treated with CRT had significantly reduced white-matter integrity, as measured by MRI fractional anisotropy (FA), and poorer neurocognitive function (lower intelligence quotient, poorer visuomotor accuracy, stability, and sequential working memory, and poorer work flow during sustained attention). Decreases in FA were observed in chemotherapy-only patients, but those decreases were more moderate than in CRT-treated survivors. Consistent with other reports describing white-matter integrity during childhood and adolescence, younger patient age at the time of CRT and higher dose were associated with worse white-matter integrity. Steep declines in FA in the frontal and parietal white matter were observed related to age of assessment, suggesting an accelerated pattern of aging. To emphasize this point, the authors note anatomic similarities between these long-term ALL survivors and aging patients with cognitive decline or dementia. Accelerated aging of the CNS is a concern of late-effects investigators. Evidence is growing for persistent neurocognitive impairment after both CRT and systemic chemotherapy in survivors of cancers involving treatment of the CNS with CRT, chemotherapy, or combination CRT and chemotherapy. Impairment is most frequently seen in the areas of executive function, processing speed, and short-term or working memory. There is additional risk for increased severity in other areas of cognitive function in children who are younger at time of treatment or who receive higher doses of CRT. For children, school performance is often negatively affected; little is known about daily-function challenges in adult survivors. Treatment of childhood ALL has changed dramatically over the last 30 years, particularly CNS prophylaxis. Before 1985, with the introduction of Pediatric Oncology Group 8602 study, children with B-lineage or T-lineage ALL were typically treated with craniospinal radiation therapy, sometimes alone and sometimes in combination with intrathecal methotrexate. The dose of CRT was typically 24 Gy or 18 Gy. The Pediatric Oncology Group 8602 study eliminated CRT for the majority of children treated for ALL, replacing it with intrathecal methotrexate or triple intrathecal chemotherapy (methotrexate, cytarabine, and hydrocortisone). This strategy reduced some of the neuroendocrine and growth delays that had been associated with CRT, but neurocognitive deficits were still observed 3 or more years after diagnosis. Treatment for ALL since the early 1990s has included a more aggressive use of systemic methotrexate during the consolidation phase of therapy, increasing from 1 gm/m to 5 gms/m. This change, without CRT, has also resulted in reports of increased neurocognitive impairment and computed tomography and MRI evidence of primarily calcification in the CNS. For children with CNS tumors, CRT remains the backbone of therapy after surgical resection. CRT doses are typically much higher than those used in the historical and current treatment of ALL (30 Gy to 65 Gy v 18Gy or less). There have been efforts dating back to the mid-1980s to reduce the dose of CRT, delay its use, or eliminate it from treatment, but most children with high-grade malignant CNS tumors will likely be treated with CRT, either photon-beam or proton-beam. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 31 NUMBER 27 SEPTEMBER 2

Effects of antiepileptic drugs on reproductive endocrine function, sexual function and sperm parameters in Chinese Han men with epilepsy

The effects of the antiepileptic drugs sodium valproate (VPA) and levetiracetam (LEV) on reproductive endocrine function, sexual function, and spermatozoa were explored, together with their possible etiological mechanisms, in Chinese Han men with epilepsy. Following VPA treatment (n=32), luteinizing hormone and follicle-stimulating hormone levels were significantly lower than in controls (n=30). The bioactive testosterone/luteinizing hormone ratio and the prolactin level were significantly elevated in the VPA treatment group. There were no significant differences in these hormones between the LEV treatment (n=20) and control groups. The rates of sperm morphologic abnormality (head, body, and tail) were significantly higher in the VPA treatment group than the control group but did not differ significantly between the LEV treatment and control groups. The sperm motility rate was significantly lower in the VPA treatment group (grade A sperm motility rate <25%, grade A+B sperm motility rate <50%) than in controls, as well as in the LEV treatment group (grade A sperm motility rate <25%). Patients in the VPA and LEV treatment groups had lower scores on questions 1, 2 and 3 of a simplified International Index of Erectile Function Scale than controls, but no significant difference on questions 4 or 5. The total International Index of Erectile Function Scale scores were significantly lower in the VPA and LEV treatment groups. We conclude that treatment with VPA adversely affects reproductive endocrine function, sperm parameters and sexual function to varying degrees in Chinese men with epilepsy.

Antioxidants enhance the recovery of three cycles of bleomycin, etoposide, and cisplatin–induced testicular dysfunction, pituitary-testicular axis, and fertility in rats

To investigate the effects of an antioxidant cocktail (AC) on bleomycin, etoposide, and cisplatin (BEP)-induced testicular dysfunction. In vivo study. Research laboratory. Adult male and female Sprague-Dawley rats. The rats were treated with three cycles of 21 days each of therapeutically relevant dose levels of BEP (0.75, 7.5, and 1.5 mg/kg) with or without the AC (a mixture of α-tocopherol, L-ascorbic acid, Zn, and Se). Sperm parameters, fertility, serum hormone levels (ELISA), testicular histopathology, and expression of proliferating cell nuclear antigen (PCNA), and transferrin (Western blotting and immunohistochemistry) were evaluated at the end of treatment and a 63-day recovery period. At the end of treatment, the AC improved BEP-induced decrease in sperm motility and increase in abnormality but had no effect on reduced sperm count, fertility, and tubular atrophy, although it up-regulated germ cell proliferation. The AC normalized reduced inhibin B levels, but had no effect on decreased transferrin and testosterone and elevated LH levels. At the end of the recovery period, the AC enhanced the expression of PCNA and transferrin, repopulation of germ cells, LH-testosterone axis, and fertility, but had no effect on reduced FSH and elevated inhibin B levels. The antioxidants protect and then enhance the recovery of testicular and reproductive endocrine functions when administered concomitantly with BEP therapy. The AC may be beneficial to regain testicular functions after chemotherapy.

Aerobic Exercise Training Attenuates Obesity-Related Hypogonadism in Male Rats

Hypogonadism is associated with obesity and other features of metabolic syndrome in males. The purpose of this study was to compare lean and obese male Zucker rats on their reproductive endocrine function in response to aerobic exercise training. Lean (Fa/Fa) and obese (fa/fa) male Zucker rats at 2 months of age were randomly assigned to a sedentary and an aerobic exercise training group (lean sedentary, n = 7; lean exercise, n = 8; obese sedentary, n = 7; obese exercise, n = 7). The exercise group walked on a rat treadmill, starting at 10 m · min(-1) for 20 min and building up to 20 m · min(-1) for 60 min, five times per week for 8 wk. Serum levels of total and free testosterone and testicular levels of testosterone, as well as epididymal and inguinal adipose tissue monocyte chemotactic protein 1 release levels, were measured. There were significant obesity-by-exercise interactions on serum levels of total and free testosterone and testicular levels of testosterone (all P < 0.05). Compared to lean sedentary rats, obese sedentary rats had lower serum and testicular testosterone levels (0.72- to 0.74-fold, all P < 0.001). There were no group differences between lean sedentary and lean exercise rats on serum and testicular testosterone levels. However, compared to the obese sedentary group, the obese exercise group had higher serum and testicular testosterone levels (1.37- to 1.47-fold, all P < 0.05). In the whole cohort, serum and testicular testosterone levels were inversely related to epididymal adipose tissue monocyte chemotactic protein 1 secretion (r = -0.40 to r = -0.45, all P < 0.05). Our results support that aerobic exercise training could improve severe obesity-related hypogonadism in male Zucker rats. The underlying mechanism needs to be further clarified.

Changes in the reproductive endocrine function in rat following intraovary microinjection of inhba overexpression lentivirus vectors

Objective: To investigate the reproductive endocrine changes after inhba overexpression into rat ovary.Method: Thirty Sprague-Dawley rats were randomly assigned to three groups. Inhba overexpression lentivirus vectors (LV-eGFP-inhba) were microinjected into rat ovary (INH group); Control animals received the same amount lentivirus vector empty (CON group) or LV-eGFP (GFP group). Antral follicle amount and diameter were counted and serum level of activin A, E2, P, FSH, and LH and the expression of ER-α, ER-β, PR, FSHR, and LHR were measured.Results: There was no significant difference among three groups in antral follicle amount; antral follicle diameter was increased in INH group rats compared with the other group rats. Serum levels of activin A, E2, P, and FSH were increased and LH was decreased in INH group rats compared with the other group rats. The mRNA and protein expression of ER-α, ER-β, FSHR was higher in INH group rats than that in the other group rats. There was no significant difference in mRNA and protein expression of PR among the three group rats, LHR expression was decreased in INH group rats compared with the other two group rats.Conclusion: inhba overexpression in rat ovary in vivo may change reproductive endocrine function.

Mode of action of human pharmaceuticals in fish: The effects of the 5-alpha-reductase inhibitor, dutasteride, on reproduction as a case study

In recent years, a growing number of human pharmaceuticals have been detected in the aquatic environment, generally at low concentrations (sub-ng/L–low μg/L). In most cases, these compounds are characterised by highly specific modes of action, and the evolutionary conservation of drug targets in wildlife species suggests the possibility that pharmaceuticals present in the environment may cause toxicological effects by acting through the same targets as they do in humans. Our research addressed the question of whether or not dutasteride, a pharmaceutical used to treat benign prostatic hyperplasia, may cause adverse effects in a teleost fish, the fathead minnow (Pimephales promelas), by inhibiting the activity of both isoforms of 5α-reductase (5αR), the enzyme that converts testosterone into dihydrotestosterone (DHT). Mammalian pharmacological and toxicological information were used to guide the experimental design and the selection of relevant endpoints, according to the so-called “read-across approach”, suggesting that dutasteride may affect male fertility and steroid hormone dynamics. Therefore, a 21-day reproduction study was conducted to determine the effects of dutasteride (10, 32 and 100μg/L) on fish reproduction. Exposure to dutasteride significantly reduced fecundity of fish and affected several aspects of reproductive endocrine functions in both males and females. However, none of the observed adverse effects occurred at concentrations of exposure lower than 32μg/L; this, together with the low volume of drug prescribed every year (10.34kg in the UK in 2011), and the extremely low predicted environmental concentration (0.03ng/L), suggest that, at present, the potential presence of dutasteride in the environment does not represent a threat to wild fish populations.

A time-course analysis of effects of the steroidogenesis inhibitor ketoconazole on components of the hypothalamic-pituitary-gonadal axis of fathead minnows

The objective of this study was to evaluate temporal effects of the model steroidogenesis inhibitor ketoconazole (KTC) on aspects of reproductive endocrine function controlled by the hypothalamic-pituitary-gonadal (HPG) axis in the fathead minnow (Pimephales promelas). Ketoconazole inhibits the activity of two cytochrome P450s (CYPs) key to sex steroid production in vertebrates, CYP11a (cholesterol side chain cleavage) and CYP17 (c17α-hydroxylase/17, 20-lyase). Sexually mature fish were exposed to water-borne KTC (30 or 300μg/L) in a flow-through system for up to 8d, following which animals were allowed to recover in clean water. Fish were sampled after 1, 4 and 8d of exposure, and after 1, 8 and 16d of recovery. A shorter-term time-course experiment also was conducted in which females were sampled on seven occasions during a 12h KTC exposure. Ketoconazole consistently depressed ex vivo gonadal synthesis of testosterone (T) in both sexes, and 17β-estradiol (E2) in females during both exposure and recovery phases of the time-course studies. Effects on ex vivo steroidogenesis in females occurred within as little as 1h of exposure. Plasma concentrations of T in males and E2 in females also were depressed by exposure to KTC, but these decreases did not persist to the same degree as observed for the ex vivo effects. In females, after decreases within 12h, plasma E2 concentrations were similar to (or greater than) controls at 24h of exposure, while in males, plasma T returned to levels comparable to controls within 1d of cessation of KTC exposure. The discrepancy between the ex vivo and in vivo data at later stages in the test is consistent with some type of compensatory response to KTC in fish. However, we were unable to ascertain the mechanistic basis for such a response. For example, although a number of genes related to steroid synthesis (e.g., cyp11a, cyp17) were up-regulated in the gonads of both males and females during the exposure and early recovery phases of the experiment, this did not seem to account for the resurgence in plasma steroid concentrations in KTC-exposed fish. Further studies focused on metabolism and clearance of steroids might lend insights as to the effects of KTC on plasma steroid concentrations. Overall, our results demonstrate the complex, temporally dynamic nature of the vertebrate HPG system in response to chemical stressors.

LW-AFC Improved or Restored the Disturbance of Reproductive Endocrine and Immune Function in Stress-Loaded Mice

There are no effective and reliable anti-stress drugs. Traditional Chinese Medicine Liu Wei Di Huang Decoction (LW) can interfere with the various types of stress-induced endocrine and immune imbalance. However, traditional LW lacks reliable quality control methods, and the reliability of its clinical efficacy is difficult to estimate. In our previous study we evaluated the immune and endocrine activity of different parts from LW separation, and then formed LW-AFC which has satisfactory quality control, security and activity. In this paper, we observe the impact of LW-AFC on the reproductive endocrine and immune system of suspension-stressed female mouse. The results show that the stress increased the serum cortisone, reduced estrus cycle, prolonged diestrus, decreased the pituitary LH, but increased serum E2 on diestrus cycle, and IgG in spleen cell culture supernatant was significantly reduced after suspension stress. LW-AFC could significantly decrease the cortisone level, increase pituitary LH, lower serum E2 on diestrus cycle, and could significantly enhance the ability of spleen cells secreting IgG. These results suggest that stress can lead to reproductive endocrine disorders and decreased immune function, and oral administration of LW-AFC may significantly regulate the stress-induced reproductive endocrine disorders and decreased immune function, which might be developed as a potential new anti-stress drugs.

Influence of low-level lead and cadmium exposure on reproductive health in men

Purpose: There is increasing evidence that occupational and environmental exposure to toxic pollutants may account for the recent declining fertility in men by reducing sperm count and testis function. Lead and cadmium are known reproductive toxicants that accumulate in the human body over a lifetime. In the most of published data, attention has usually been directed towards excessive exposure to these metals. Very few epidemiologic studies have attempted to investigate the influence of low-level lead and cadmium exposure on reproductive health in men. Methods: Blood lead and cadmium, serum zinc, copper and selenium, parameters of semen quality and of reproductive endocrine function were measured in 280 non-smoking men with no occupational exposure to metals. The interrelationship of all the measured parameters, including age and alcohol consumption, was calculated by forward stepwise multiple regression. Results of the study: The median and range values for blood lead were 32 (6-149) ug/L and for cadmium 0.34 (<0.05-3.7) ug/L. After adjusting for potential confounding variables, blood lead was significantly associated with an increase in testosterone (P<0.005) and immature sperm concentration (P<0.002) and a decrease in percentages of slight amorph sperm (P<0.0001), whereas blood cadmium was significantly associated with an increase in percentage of slow sperm (P<0.005). These results indicate that even low-level lead and/or cadmium exposure may have adverse effects on male reproductive health.

Unique bioactivities of bone morphogenetic proteins in regulation of reproductive endocrine functions.

Remarkable progress has been made in understanding the mechanism by which growth factors and oocytes can regulate the development and function of granulosa cells. Insufficiency of two oocyte-specific growth factors, growth differentiation factor-9 and bone morphogenetic protein (BMP)-15, cause female infertility. Expression of mRNA and/or protein for the BMP system components, including ligands, receptors and intracellular signal transduction factors, was demonstrated in cell components of growing preantral follicles, and biofunctional experiments have further revealed many important roles of the BMP system in regulation of reproductive function. In this review, recent advances in studies on biological actions of BMPs in ovarian folliculogenesis and in related endocrine tissues are discussed.

Experimental Study on Acupuncture Activating the Gonadotropin-releasing Hormone Neurons in Hypothalamus

To probe into the most effective site, extra-ordinary point, acupoint and channel for regulating reproductive endocrine function by means of the study on acupuncture activating the gonadotropin-releasing hormone neurons (GnRH) in hypothalamus. Female SD rats of reproductive age were used, and the in vivo study on GnRH neurons in hypothalamus was made with mimic sexual stimulation and feedback regulation. The neuron-activating effects of the acupoints on the channels pertaining to the zang- and fu-organs related with reproductive endocrine and the extra-ordinary points in different regions were studied using the discharge of the neuron as index, and then the neurons were labeled with horseradish peroxidase (HRP). Acupuncture was given at two acupoints each on the three yin channels of foot, the three yang channels of foot, the Conception Vessel and the Governor Vessel. The order of the mean increasing percentage in the hypothalamic GnRH neuron electric activity was: the Gallbladder Channel > the Spleen Channel > the Stomach Channel/the Bladder Channel/the Conception Vessel > the Liver Channel > the Kidney Channel > the Governor Vessel; for different acupoints, it was: Guanyuan (CV 4) > Sanyinjiao (SP 6) > Zusanli (ST 36) > Daimai (GB 26)/Yanglingquan (GB 34) > Shenshu (BL 23) > Weizhong (BL 40) > Yaoyangguan (GV 3)/Liangmen (ST 21)/Fujie (SP 14) > Qimen (LR 14)/Yingu (KI 10) > Tangzhong (CV 17)/Zhiyang (GV 9); for different positions, it was: the lower abdominal part/the lower limb part > the thoracodorsal part; for the extra-ordinary points, it was: Zigong (EX-CA1) > Dannang (EX-LE6)/Yaoyan (EX-B7) > Baichongwo (EX-LE3)/Qianzheng > Jingbi/Bizhong/Taiyang (EX-HN5) > Erbai (EX-UE2)/ Dingchun; and for the distribution sites of the extra-ordinary points: lower abdominal region > the lower limb region > the craniofacial region > the upper limb region/the thoracodorsal region. For regulating the reproductive endocrine function, the acupoints located at the same neural segment with the reproductive organ should be selected as the main points, and it is necessary to combine with syndrome differentiation of the viscera and channels.

Effects of levetiracetam and valproic acid monotherapy on sex-steroid hormones in prepubertal children—Results from a pilot study

The influence of levetiracetam (LEV) and valproic acid (VPA) monotherapy on sex-steroid hormone profile was investigated in thirty prepubertal children. VPA-treated children showed greatest androstendione concentrations when compared to LEV treated children (p=0.016) and to controls (p=0.011). All other reproductive endocrine hormones were similar among groups. In conclusion, LEV does not seem to induce changes in reproductive endocrine functions as well as clinically relevant endocrine side effects in prepubertal children.

Ovarian function 6years after cryopreservation and transplantation of whole sheep ovaries

Whole ovary cryopreservation and transplantation has been proposed as a method for preserving long-term ovarian function. This work reports ovarian function 6years post transplantation of frozen-thawed whole sheep ovaries. Three 9-month-old Assaf sheep underwent unilateral oophorectomy to provide organs for the experiments. After perfusing with cold University of Wisconsin solution supplemented with 10% dimethyl sulphoxide, ovaries were cryopreserved using unidirectional solidification freezing technology. After thawing, ovaries were re-perfused and re-transplanted orthotopically by microvascular re-anastomosis, to the contralateral ovarian pedicle after removing the remaining ovary. Six years following transplantation and after inducing superovulation, the sheep were killed and the ovaries analysed. Two ovaries had normal size and shape showing some recent corpora lutea, while the third showed atrophic changes. A total of 36 antral follicles were counted by transillumination and four germinal vesicle oocytes were aspirated and matured in vitro to metaphase II. Serum progesterone concentrations were indicative of ovulatory activity in one of the three sheep. Histological evaluations revealed normal tissue architecture, intact blood vessels and follicles at various stages. Currently, this is the longest recorded ovarian function after cryopreservation and re-transplantation. Cryopreservation of whole ovaries, using directional freezing combined with microvascular anastomosis, is a promising method for preserving long-term reproductive capacity and endocrine function.

Ovarian Tissue Autologous Transplantation to the Upper Extremity for Girls Receiving Abdominal/Pelvic Radiation: 20-year Follow-up of Reproductive Endocrine Function

Objective Upper-extremity ovarian autologous transplantation was first used for girls undergoing abdominal/pelvic radiation therapy; long-term follow-up is provided. Design A case series. Setting Tertiary pediatric medical center. Patients Girls with Wilms tumor with planned abdominal/pelvic radiation therapy. Interventions Subjects 1, 2, and 3 (ages 5, 2, and 1 year) presented with a Wilms tumor and underwent surgical resection. Each patient underwent ovarian autotransplantation to move ovarian tissue out of the radiation field. Subjects 1 and 2 had thin slices from 1 ovary placed in the arm. Subject 3 had a free transfer of the entire ovary into an axilla. Follow-up was obtained for the subsequent 20-25 years for all 3 subjects. Outcome Measures Pubertal, menarcheal, and menstrual history, and hormonal serum levels. Results All subjects survived and experienced spontaneous pubertal development and menarche. Data were available for follow-up for 20-25 years. Subjects 1 and 2 showed spontaneous follicular development of the autotransplanted ovarian tissue. They had fluctuating gonadotropin and estradiol levels until age 29 and 26, respectively; spontaneous menses until age 29 and 26; and cessation of spontaneous menses with elevated gonadotropins and low estradiol levels at age 30 and 26. Subject 3 had severe monthly axillary pain, and the ovary was transferred back to the pelvis. She then had ovarian dysfunction with intermittent spontaneous ovarian activity until age 25. Conclusions Ovarian autotransplantation to the upper extremity resulted in long-term sex steroid production for spontaneous puberty, menarche, follicular development, and menses with fluctuating gonadotropin and ovarian sex steroid levels and follicular activity that lasted for 13-15 years.

Differential effects of levetiracetam, carbamazepine, and lamotrigine on reproductive endocrine function in adults

Animal studies have shown endocrine changes after levetiracetam treatment. The present study investigated reproductive and sexual function in patients with epilepsy (aged 18–45) treated with levetiracetam (LEV: 30 men/26 women), carbamazepine (CBZ: 63 men/30 women), or lamotrigine (LTG: 37 men/40 women) monotherapy and in healthy controls (36 men/44 women). In women, no endocrine changes were observed during LEV treatment, whereas steroid hormone-binding globulin levels were greater and progesterone levels lower in women using CBZ. Dehydroepiandrosterone sulfate levels were higher and androstenedione levels lower in LTG-treated women. Arizona Sexual Experience Scale scores, which were significantly lower in females using LTG or LEV, suggesting they have better sexual function than CBZ users and controls. In men, no drug-specific hormonal pattern was observed after LEV treatment. Male patients in all treatment groups had lower androstenedione and free testosterone. Those using CBZ had lower free androgen indices and dehydroepiandrosterone sulfate levels, and higher steroid hormone-binding globulin, follicle-stimulating hormone, and luteinizing hormone levels. Arizona Sexual Experience Scale scores for men were similar in all groups. In conclusion, LEV treatment apparently has no drug-specific sexual or endocrine side effects in men or women in this age group.