The postnatal presence of human chorionic gonadotropin in preterm infants and its potential inverse association with retinopathy of prematurity.

BACKGROUND: Human chorionic gonadotropin (hCG) and luteinizing hormone (LH) are pro-angiogenic gonadotropic hormones, which classically target the reproductive organs. However, hCG, LH, and their shared CG/LH receptor are also present in the human eye. The possibility that a deficiency of these hormones may be involved in the pathogenesis of retinopathy of prematurity (ROP) during its early non-proliferative phase has not been explored. METHODS: We conducted a cross-sectional study of Michigan-born preterm infants utilizing dried blood spots. We analyzed hCG and LH blood levels at 1 week and 4 weeks of age from 113 study participants (60 without ROP; 53 with non-proliferative ROP). We utilized electrochemiluminescence assays on the Mesoscale Discovery platform. RESULTS: Similar levels of hCG are found in preterm infants at both 1 week and 4 weeks after birth. Preterm infants with non-proliferative ROP, after adjusting for sex and gestational age, have 2.42 [95% CI: 1.08-5.40] times the odds of having low hCG at fourth week of age. CONCLUSIONS: We found that hCG is present postnatally in preterm infants and that a deficiency of hCG at 4 weeks of age is potentially associated with non-proliferative ROP. This provides novel evidence to suggest that hCG may participate in human retinal angiogenesis.

Long-term outcome of patients with persistent low-level elevation of human chorionic gonadotrophin.

AIM: The aim of this study was to investigate a series of patients with sustained low-level elevated human chorionic gonadotrophin (hCG) and explore the management of these patients. METHODS: A total of 47 patients with persistent low levels of hCG were selected for analysis between January 2002 and January 2014 at the Women's Hospital of Zhejiang University, Hangzhou, China. Data were retrospectively reviewed for patient characteristics, therapeutic strategies, and follow-ups. We compared the characteristics of patients who were and were not eventually considered to have malignancies. RESULTS: Among the 47 patients, 17 with persistent low-level elevated hCG and no detectable lesions were considered to have no active malignancy. Fifteen of the 17 patients had hCG levels that returned to normal range by the end of follow-up, while the remaining two did not. The other 30 patients were eventually diagnosed as having active malignancies due to detected lesions or increasing elevation of hCG. A large proportion of these patients were diagnosed with placental site trophoblastic tumor or epithelioid trophoblastic tumor. CONCLUSION: For patients with persistent low-level elevated hCG, frequent follow-up rather than any therapy is recommended. Treatment was considered effective and safe once diagnosis of active malignancy was confirmed.

Human chorionic gonadotropin attracts regulatory T cells into the fetal-maternal interface during early human pregnancy.

Regulatory T cells (Treg) expand during pregnancy and are present at the fetal-maternal interface at very early stages in pregnancy. The migration mechanisms of Treg to the pregnant uterus are still unclear. Human chorionic gonadotropin (hCG) is secreted by the blastocyst immediately after fertilization and has chemoattractant properties. Therefore, we sought to analyze whether hCG secreted by early trophoblasts attracts Treg to the uterus and hence contributes to maternal tolerance toward the fetus. Decidua and placenta tissue samples from patients having spontaneous abortions or ectopic pregnancies were employed to evaluate Treg and hCG levels. Age-matched samples from normal pregnant women served as controls. We further performed in vitro studies with primary first trimester trophoblast cells and a choriocarcinoma cell line (JEG-3) aiming to evaluate the ability of secreted hCG to attract Treg. Patients having miscarriages or ectopic pregnancy presented significantly decreased hCG mRNA and protein levels associated with decreased Foxp3, neuropilin-1, IL-10, and TGF-beta mRNA levels as compared with normal pregnant women. Using migration assays we demonstrated that Treg were attracted by hCG-producing trophoblasts or choriocarcinoma cells. Treg migration toward cells transfected with hCG expression vectors confirmed the chemoattractant ability of hCG. Our data clearly show that hCG produced by trophoblasts attracts Treg to the fetal-maternal interface. High hCG levels at very early pregnancy stages ensure Treg to migrate to the site of contact between paternal Ags and maternal immune cells and to orchestrate immune tolerance toward the fetus.

[Persistent low levels of human chorionic gonadotropin in the serum: investigation and management].

Persistent low levels of human Chorionic Gonadotropin-hCG, the pregnancy hormone, in the serum in the absence of pregnancy or any evidence of Gestational Trophoblastic Disease (GTD) is a diagnostic and therapeutic dilemma. This condition mostly presents during follow-up after patients with a history of GTD or hydatidiform mole or an incidental pregnancy test. Many physicians are not aware of the broad differential diagnosis of this condition which is mostly benign. Therefore, many women with this condition have received chemotherapy and hysterectomy for assumed malignancy which were ineffective and unwarranted. The most common etiologies are: 1. Pituitary hCG: A condition mostly found in older women, completely benign and can be resolved using hormone replacement therapy or oral contraceptives. 2. False positive hCG: this condition has no clinical meaning, it can be identified by the absence of hCG in a parallel urine sample or using a better hCG test with no past reports of false positive. 3. Quiescent GTD: This is a benign trophoblastic disease in which the hyperglycosylated hCG accounts for a small percentage of the total hCG in the serum. Due to its premalignant nature, a follow-up of the hCG levels and the hyperglycosylated hCG percentage is needed. The hCG molecule has many forms. Different hCG tests detect different forms identified as heterogeneous in nature. For each etiology mentioned above there is a characteristic dominant form. If it was known which test to use, the diagnosis could be made.

Phenotypic characterisation of mice with exaggerated and missing LH/hCG action.

In order to study the physiology and pathophysiology of gonadotrophin action, we have produced transgenic (TG) mice overexpressing human chorionic gonadotrophin (hCG) alpha and beta subunits (hCG+ mice) and knockout (KO) mice for the luteinising hormone receptor (LHR; LuRKO mice). The two extremes in LH function, i.e. strong LH/hCG stimulation and total blockade of this action, confirm numerous earlier concepts about LH function, but they also reveal new aspects about gonadal function during excessive LH production and in the absence of this trophic stimulus. The purpose of this review is to summarise the key findings on these two genetically modified mouse models.

[Management of an ovarian stimulation in case of a Kallmann-De Morsier syndrome. The role of LH]. / Prise en charge en induction de l'ovulation d'un cas de syndrome de Kallmann-De Morsier. Réflexions sur le rôle de la LH.

We report a case of ovarian stimulation in a woman with a Kallmann-De Morsier syndrome, which resulted in a triple pregnancy and childbirth by caesarean section at 36 weeks of amenorrhea of three girls weighing from 1,950 to 2,300 g. Starting from a literature review of Kallmann-De Morsier syndrome, we discuss the role of LH during the follicular phase and the monitoring of ovarian stimulation.

A syndrome of functional hypogonadotropic hypogonadism and sterility in a male with elevated serum estradiol.

A 36-year-old male complaining of impotence was examined. He was a genotypic male. Phenotypically, he exhibited signs of long-standing estrogen excess, such as feminine body build, gynecomastia, and varicose veins. His testes were soft and borderline small, and his prostate was small and soft. However, he had a normal-sized penis, normal male hair distribution, normal sense of smell, and normal intelligence. The laboratory data were compatible with mild hypogonadotropic hypogonadism. Serum estradiol (E2) levels were consistently elevated. The patient had azoospermia and a decreased semen volume. Inappropriately low levels of luteinizing hormone and follicle-stimulating hormone responded normally to gonadotropin-releasing hormone and clomiphene citrate. Levels of both testosterone (T) and E2 increased dramatically after prolonged clomiphene medication and in response to human chorionic gonadotropin. There was no change in either T or E2 levels in response to manipulations of the pituitary-adrenal axis. It is concluded that the elevated E2 level was responsible for suppression of gonadotropins which, in turn, caused mild hypogonadism and sterility in this patient. According to the stimulation tests, the source of the elevated E2 levels was testicular.

[Turner's phenotype in a male with deficit of ACTH and gonadotropins (author's transl)]. / Fenotipo Turner en un varón con déficit de gonadotropinas y ACTH.

A case of male Turner's syndrome in a 23-year-old patient is reported. Clinical features included total eunuchoidism, shield-like chest, cubitus valgus, lymphedema in the extremities (hands and feet) and a shortened fourth metacarpal. Hormonal studies revealed very low levels of gonadotropins, cortisol, testosterone and HGH, and normal values for PRL and TSH. Gonadotropin levels did not change after the administration of 100 micrograms LH-RH and 500 micrograms LH-RH every 8 hours during 5 days. Testosterone levels increased when HCG was given. Deficit of ACTH release was demonstrated after the administration of metopyrone, ACTH and 0.1 UI insulin per kilogram of body weight to induce hypoglycemia. Hypoglycemia with insulin and arginine did not determine an increase of GH levels, instead of previous estrogen therapy. These results reveal a hypophyseal hormonal defect in relation to ACTH, LH, FSH and GH release. Hormone abnormalities found in the present case have not been previously described.

Male reproductive endocrinology: when to replace gonadotropins.

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

Mechanism of human chorionic gonadotrophin-mediated immunomodulation in pregnancy.

Human chorionic gonadotrophin (hCG) is released within hours of fertilization and has a profound ability to downregulate maternal cellular immunity against trophoblastic paternal antigens. It also promotes angiogenic activity of the extravillous trophoblast, and impairment of this function may lead to inadequate placentation and an increased risk of preeclampsia. There is increasing evidence that hCG alters the activity of dendritic cells via an upregulation of indoleamine 2,3-dioxygenase activity. This reduces T-cell activation and cytokine production, as well as encouraging Treg cell recruitment to the fetal-maternal interface. These changes are critical in promoting maternal tolerance. hCG is also able to increase the proliferation of uterine natural killer cells, while reducing the activity of cytotoxic peripheral blood natural killer cells. There are rare reports of autoantibodies directed against hCG or the luteinizing hormone/hCG receptor in women with recurrent miscarriage. These autoantibodies are more frequent in women with thyroid autoimmunity. This may explain the association between thyroid autoimmunity and impaired fertility. Downregulating these anti-hCG and anti-luteinizing hormone/hCG receptor autoantibodies may be helpful in some women with early miscarriage or recurrent failed in vitro fertilization.

Transient upregulation of indoleamine 2,3-dioxygenase in dendritic cells by human chorionic gonadotropin downregulates autoimmune diabetes.

OBJECTIVE: Pregnancy induces a state of immunological tolerance that aims at suppressing immune responses against the fetus and has been linked to temporal remission of preexisting autoimmune disorders. To understand the mechanisms of this reversible immune regulation, we investigated the role of a key pregnancy hormone, human chorionic gonadotropin (hCG), in immune tolerance against autoimmune type 1 diabetes in nonobese diabetic (NOD) mice. RESEARCH DESIGN AND METHODS: We injected hCG into cytokine gene-deficient NOD mice and evaluated the effects of hCG administration on T-cells and dendritic cells (DCs). RESULTS: We show that administration of hCG to NOD mice inhibits both the activation of diabetogenic CD4(+) and CD8(+) T-cells, in vitro and in vivo, and the progression of type 1 diabetes by upregulating the expression of indoleamine 2,3-dioxygenase (IDO) in DCs. IDO upregulation is transient and declined shortly after hCG withdrawal. DC depletion restores the diabetetogenic activity of splenic T-cells from hCG-treated mice, and inhibition of IDO activity by 1-methyl-tryptophan abrogates the hCG-induced T-cell suppression and resistance to type 1 diabetes. CONCLUSIONS: We propose that hCG-induced upregulation of IDO in DCs plays a major role in pregnancy-associated resistance to autoimmunity.

[Use of Soviet-made menotropin for the treatment of hypogonadotropic hypogonadism in women]. / Primenenie otechestvennogo preparata manopauznogo gonadotropina dlia lecheniia gipogonadotropnogo gipogonadizma u zhenshchin.

Investigation of the therapeutic efficacy of menopause gonadotropin (MPG), made in the USSR, in patients with hypogonadotropic hypogonadism demonstrated MPG to possess the FSH-activity. In a number of patients with hypogonadotropic hypogonadism MPG treatment led to the occurrence of the ovular menstrual cycle, confirmed both clinically and by hormonal studies. But sometimes MPG proved to be ineffective, this pointing to the necessity of individual choice of a drug dose and the number of therapeutic courses.

The role of thyrotrophin releasing hormone in the diagnosis of isolated gonadotrophin deficiency.

We studied the response of PRL and TSH to thyrotrophin-releasing hormone (TRH) in 15 boys with delayed adolescence and 6 male subjects with isolated gonadotrophin deficiency (IGD). TRH tests were repeated in the IGD subjects during and 1 month following hCG treatment. Male IGD subjects showed a significantly decreased basal and TRH induced PRL response compared to male controls and subjects with delayed adolescence. Human chorionic gonadotrophin (HCG) treatment of male IGD subjects restored basal and stimulated PRL levels to the range of normal controls. This was, presumably, an estrogenic effect since non aromatizable androgens did not increase the PRL response; moreover, the antioestrogen, clomiphene, decreased the PRL response when given with HCG. The TSH response to TRH in delayed adolescents was increased as compared to adult male controls and IGD subjects and was similar to adult female controls. HCG treatment of IGD subjects had no effect on basal nor peak TSH levels, although ethinyl oestradiol did increase the TSH response in two IGD subjects. These studies show that the PRL and TSH responses to TRH may differentiate delayed adolescence from IGD. The increased TSH response to TRH in delayed adolescence as compared to adult males, is a manifestation of an enhanced oestrogen effect in these patients. The abnormal PRL dynamics in IGD is a consequence of estrogen deficiency.

Treatment of growth hormone insufficiency.

Growth during childhood is growth hormone dependent and is modulated predominantly by the amplitude of the growth hormone secretory bursts while the frequency of these episodes remains relatively constant at 180-200 min. Optimisation of therapy for children with growth hormone insufficiency requires a clear definition of the dose of the growth hormone required to promote growth which in severely insufficient children is at least 20 U/m2 body surface area/week. The frequency of administration of growth hormone is equally important in determining response, and interpretation of any result of therapy condition that is being treated also needs to be carefully considered. Children with Turner's syndrome will not have the same growth response as children who have classical growth hormone insufficiency.

Leydig cell differentiation induced by stimulation with HCG and HMG in two patients affected with hypogonadotropic hypogonadism.

In order to elucidate the ultrastructural characteristics of the precursor cell of Leydig cells and its subsequent differentiation, testicular biopsies from two patients with hypogonadotropic hypogonadism, obtained prior to and after treatment with HCG and HMG, were studied in comparison with those of prepubertal, pubertal and postpubertal testes. Prior to HCG and HMG stimulation, the testicular interstitium of both patients showed the following spindle-cell-types: Fibroblasts, myofibroblasts and a cell-type similar to the myofibroblast but differing from it by the arrangement of microfilaments and the development of the smooth endoplasmic reticulum as well as lipid droplets. It may be considered the precursor of Leydig cells. In the following stages of differentiation observed in the biopsies after treatment, there is a progressive involution of microfilaments and rough endoplasmic reticulum, a transient period of hyperplasia of the Golgi complex, and the definitive development of cell components involved in steroid biosynthesis, such as the smooth endoplasmic reticulum, polymorphic mitochondria with tubular cristae, lipid droplets and diverse lysosomal bodies. From early stages of differentiation, gap junctions occurred between the cells. Numerous axon profiles were also present among the cells. Only in a small percentage of cells did vesicle-bearing axons closely appose the Leydig cell membrane.