Inactivating Mutations of the Human Luteinizing Hormone Receptor in Both Sexes

The human luteinizing hormone/chorionic gonadotropin receptor (LHCGR) plays a fundamental role in male and female reproductive physiology. Over the past 15 years, several homozygous or compound heterozygous loss-of-function mutations in the LHCGR gene have been described in males and females. In genetic males, mutations in LHCGR were associated with distinct degrees of impairment in pre- and postnatal testosterone secretion resulting in a phenotypic spectrum. Patients with the severe form of LH resistance have predominantly female external genitalia and absence of secondary sex differentiation at puberty. Patients with milder forms have predominantly male external genitalia with micropenis and/or hypospadias or only infertility without ambiguity. The undermasculization is associated with low basal, as well as human CG-stimulated, testosterone levels and elevated LH levels after pubertal age, without abnormal step-up in testosterone biosynthesis precursors. The testes have only slightly reduced size but mature Leydig cells are absent or scarce (Leydig cell hypoplasia). Genetic females with inactivating LHCGR mutations have female external genitalia, spontaneous breast and pubic hair development at puberty, and normal or late menarche followed by oligoamenorrhea and infertility. Estradiol and progesterone levels are normal for the early to midfollicular phase, but do not reach ovulatory or luteal phase levels. Serum LH levels are high whereas follicle-stimulating hormone levels are normal or only slightly increased. Pelvic ultrasound has demonstrated a small or normal uterus and normal or enlarged ovaries with cysts. The inactivating mutations of the LHCGR have provided important insights into distinct physiological roles of LH in reproduction of both sexes.

Dynamics of follicular growth and progesterone concentrations in cyclic and anestrous suckling Nelore cows (Bos indicus) treated with progesterone, equine chorionic gonadotropin, or temporary calf removal

The objective of this study was to investigate the effects of eCG and temporary calf removal (TCR) associated with progesterone (P4) treatment on the dynamics of follicular growth, CL size, and P4 concentrations in cyclic (n ¼ 36) and anestrous (n ¼ 30) Nelore cows. Cyclic (C) and anestrous (A) cows were divided into three groups. The control group received 2 mg of estradiol benzoate via intramuscular (IM) injection and an intravaginal device containing 1.9 g of P4 on Day 0. On Day 8, the device was removed, and the animals received 12.5 mg of dinoprost tromethamine IM. After 24 hours, the animals received 1 mg of estradiol benzoate IM. In the eCG group, cows received the same treatment described for the control group but also received 400 UI of eCG at the time of device removal. In the TCR group, calves were separated from the cows for 56 hours after device removal. Ultrasound exams were performed every 24 hours after device removal until the time of ovulation and 12 days after ovulation to measure the size of the CL. On the same day as the CL measurement, blood was collected to determine the plasma P4 level. Statistical analyses were performed with a significance level of P ≤ 0.05. In cyclic cows, the presence of the CL at the beginning of protocol resulted in a smaller follicle diameter at the time of device removal (7.4 ± 0.3 mm in cows with CL vs. 8.9 ± 0.4 mm in cows without CL; P ¼ 0.03). All cows ovulated within 72 hours after device removal. Anestrous cows treated with eCG or TCR showed follicle diameter at fixed-timed artificial insemination (A-eCG 10.2 ± 0.3 and A-TCR 10.3 ± 0.5 mm) and follicular growth rate (A-eCG 1.5 ± 0.2 and A-TCR 1.3 ± 0.1 mm/day) similar to cyclic cows (C-eCG 11.0 ± 0.6 and C-TCR 12.0 ± 0.5 mm) and (C-eCG 1.4 ± 0.2 and C-TCR 1.6 ± 0.2 mm/day, respectively; P ≤ 0.05). Despite the similarities in CL size, the average P4 concentration was higher in the A-TCR (9.6 ± 1.4 ng/mL) than in the A-control (4.0 ± 1.0 ng/mL) and C-TCR (4.4 ± 1.0 ng/mL) groups (P < 0.05). From these results, we conclude that eCG treatment and TCR improved the fertility of anestrous cows by providing follicular growth rates and size of dominant follicles similar to cyclic cows. Additionally, TCR increases the plasma concentrations of P4 in anestrous cows

Análise dos resultados maternos e fetais dos procedimentos invasivos genéticos fetais: um estudo exploratório em Hospital Universitário

OBJETIVO: Caracterizar as indicações das gestantes que procuraram o serviço de Medicina Fetal do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo para realização de procedimentos invasivos diagnósticos e avaliar os resultados dos cariótipos fetais e de suas gestações. MÉTODOS: Estudo observacional retrospectivo das gestantes que realizaram biópsia de vilo corial (BVC), amniocentese e cordocentese no período de fevereiro de 2005 a dezembro de 2009. Não foram incluídos outros procedimentos diagnósticos ou procedimentos terapêuticos. O resultado da gestação foi obtido através de consulta de prontuário eletrônico e/ou físico e/ou contato telefônico. RESULTADOS: Foram realizados 713 procedimentos (113 BVC, 340 amniocenteses e 260 cordocenteses). A principal indicação para a realização dos procedimentos invasivos foi a presença de alterações estruturais nos fetos, seguido por valores aumentados da translucência nucal e pela idade materna avançada. O cariótipo fetal esteve alterado em 186 casos (26,1%). A trissomia do cromossomo 18 foi a aneuploidia mais comum, seguida pela trissomia do 21, a monossomia do X e a trissomia do cromossomo 13. Ocorreram 4,9% de abortamento, 25,7% de natimortos e 13% de neomortos. Oito gestantes optaram pela interrupção judicial, e 99% das gestantes cujos fetos não apresentavam malformação e que apresentavam cariótipo fetal normal tiveram nativivos.

Hydatidiform mole resulting from sexual violence

Abstract Background Hydatidiform mole (HM) is characterized by abnormal proliferation of human trophoblast with producers functioning tissues of human chorionic gonadotropin. It can evolve with ovarian cysts tecaluteínicos, hypertension of pregnancy or hyperthyroidism. The incidence of HM is variable and its etiology poorly known, associated with nutritional factors, environmental, age, parity, history of HM, oral contraceptives, smoking, consanguinity or defects in germ cells. There is no reference in literature on HM resulting from sexual violence, objective of this report. Method Description of two cases of HM among 1146 patients with pregnancy resulting from sexual violence treated at Hospital Pérola Byington, São Paulo, from July 1994 to August 2011. Results The cases affected young, white, unmarried, low educated and low parity women. Sexual violence was perpetrated by known offenders unrelated to the victims, under death threat. Ultrasound and CT of the pelvis showed bulky uterus compatible with HM without myometrial invasion. One case was associated with theca lutein cysts. The two cases were diagnosed in the second trimester of pregnancy and evolved with hyperthyroidism. There was no hypertension, disease recurrence, metastasis or sexually transmitted infection. Conclusion The incidence of HM was 1:573 pregnancies resulting from rape, within the range estimated for Latin American countries. Trophoblastic material can be preserved to identify the violence perpetrator, considering only the paternal HM chromosomes. History of sexual violence should be investigated in cases of HM in the first half of adolescence and women in a vulnerable condition.

Manipulation of follicle development to ensure optimal oocyte quality and conception rates in cattle

Over the last several decades, a number of therapies have been developed that manipulate ovarian follicle growth to improve oocyte quality and conception rates in cattle. Various strategies have been proposed to improve the responses to reproductive biotechnologies following timed artificial insemination (TAI), superovulation (SOV) or ovum pickup (OPU) programmes. During TAI protocols, final follicular growth and size of the ovulatory follicle are key factors that may significantly influence oocyte quality, ovulation, the uterine environment and consequently pregnancy outcomes. Progesterone concentrations during SOV protocols influence follicular growth, oocyte quality and embryo quality; therefore, several adjustments to SOV protocols have been proposed depending on the animal category and breed. In addition, the success of in vitro embryo production is directly related to the number and quality of cumulus oocyte complexes harvested by OPU. Control of follicle development has a significant impact on the OPU outcome. This article discusses a number of key points related to the manipulation of ovarian follicular growth to maximize oocyte quality and improve conception rates following TAI and embryo transfer of in vivo-and in vitro-derived embryos in cattle.

Video laparoscopic intervention for an interstitial pregnancy after failure of clinical treatment

CONTEXT: Interstitial pregnancy is a rare form of ectopic pregnancy for which the best therapeutic course of action has yet to be determined. Surgical intervention entails a high risk of hemorrhage due to the great vascularization of the cornual region of the uterus. Case descriptions facilitate the analysis of results and aid clinicians in determining the most appropriate course of action in these situations. CASE REPORT: In a patient with an ultrasound diagnosis of interstitial pregnancy, clinical treatment using methotrexate was chosen. However, after one week, there was a marked decline in the serum level of the β subunit of chorionic gonadotropin hormone, although an ultrasound examination revealed embryonic cardiac activity. A second dose of the chemotherapy was administered. Embryonic cardiac activity persisted 48 hours later. Video laparoscopy was performed to achieve right-side cornual resection, which resulted in satisfactory resolution of the case.

Prostaglandin treatment at the onset of norgestomet and estradiol-based synchronization protocols did not alter the ovarian follicular dynamics or pregnancy per timed artificial insemination in cyclic Bos indicus heifers

The aim of the present study was to evaluate the effects of the PGF2˛treatment givenat the onset of a synchronization of ovulation protocol using a norgestomet (NORG) earimplant on ovarian follicular dynamics (Experiment 1) and pregnancy per AI (P/AI; Exper-iment 2) in cyclic (CL present) Bos indicus heifers. In Experiment 1, a total of 46 heiferswere presynchronized using two consecutive doses of PGF2˛12 days apart. At first dayof the synchronization protocol the heifers received implants containing 3 mg of NORGand 2 mg of estradiol benzoate (EB). At the same time, heifers were randomly assignedto receive 150 mg of d-cloprostenol (n = 23; PGF2˛) or no additional treatment (n = 23;Control). When the ear implants were removed 8 days later, all heifers received a PGF2˛treatment and 1 mg of EB was given 24 h later. The follicular diameter and interval toovulation were determined by transrectal ultrasonography. No effects of PGF2˛treat-ment on the diameter of the largest follicle present were observed at implant removal(PGF2˛= 9.8 ± 0.4 vs. Control = 10.0 ± 0.3 mm; P = 0.73) or after 24 h (PGF2˛= 11.1 ± 0.4 vs.Control = 11.0 ± 0.4 mm; P = 0.83). No differences in the time of ovulation after ear implantremoval (PGF2˛= 70.8 ± 1.2 vs. Control = 73.3 ± 0.9 h; P = 0.10) or in the ovulation rate(PGF2˛= 87.0 vs. Control = 82.6%; P = 0.64) between treatments were observed. In Experi-ment 2, 280 cyclic heifers were synchronized using the same experimental design describedabove (PGF2˛; n = 143 and Control; n = 137), at random day of the estrous cycle. All heifersreceived 300 IU of equine chorionic gonadotropin (eCG) and 0.5 mg of estradiol cypionate(as ovulatory stimulus) when the NORG ear implants were removed. Timed artificial insem-ination (TAI) was performed 48 h after implant removal and the pregnancy diagnosis wasconducted 30 days later. No effects on the P/AI due to PGF2˛treatment were observed(PGF2˛= 51.7 vs. Control = 57.7%; P = 0.29). In conclusion, PGF2˛treatment at the onset ofNORG-based protocols for the synchronization of ovulation did not alter the ovarian follic-ular responses or the P/AI in cyclic Bos indicus beef heifers synchronized for TAI.

An ancient founder mutation in PROKR2 impairs human reproduction

Congenital gonadotropin-releasing hormone (GnRH) deficiency manifests as absent or incomplete sexual maturation and infertility. Although the disease exhibits marked locus and allelic heterogeneity, with the causal mutations being both rare and private, one causal mutation in the prokineticin receptor, PROKR2 L173R, appears unusually prevalent among GnRH-deficient patients of diverse geographic and ethnic origins. To track the genetic ancestry of PROKR2 L173R, haplotype mapping was performed in 22 unrelated patients with GnRH deficiency carrying L173R and their 30 first-degree relatives. The mutations age was estimated using a haplotype-decay model. Thirteen subjects were informative and in all of them the mutation was present on the same approximate to 123 kb haplotype whose population frequency is 10. Thus, PROKR2 L173R represents a founder mutation whose age is estimated at approximately 9000 years. Inheritance of PROKR2 L173R-associated GnRH deficiency was complex with highly variable penetrance among carriers, influenced by additional mutations in the other PROKR2 allele (recessive inheritance) or another gene (digenicity). The paradoxical identification of an ancient founder mutation that impairs reproduction has intriguing implications for the inheritance mechanisms of PROKR2 L173R-associated GnRH deficiency and for the relevant processes of evolutionary selection, including potential selective advantages of mutation carriers in genes affecting reproduction.