Extragonadal Effects of hCG on Calcium Homeostasis
Condition: Hypogonadism; Calcium Disorder; Renal Disease
MeSH terms: Hypogonadism
Study type: Interventional
Phase: Phase 1

Summary: 
      A pilot study showed that serum calcium levels and calcium homeostasis change in response to
      hCG stimulation test. Serum calcium level differed when comparing pretreatment values at
      baseline with serum levels 72 hours after hCG stimulation in men with gonadal insufficiency
      referred for this stimulation test. Now we want to investigate whether this change in calcium
      is due to renal loss or other mechanisms and how the classical regulators of calcium
      homeostasis respond to hCG in men with impaired gonadal function compared with men having
      normal gonadal function. Moreover, the observed change in serum calcium implies that hCG also
      changes Phosphate, PTH and calcitonin and this will be clarified with this study
    

Detailed description: 
      Aim To investigate whether human chorionic gonadotropin (hCG) stimulation test changes
      calcium-phosphate homeostasis in men with normal and impaired testicular function.

      The overall purpose of the project is to investigate the importance of human chorion
      gonadotropin (hCG) for the calcium balance in normal men and men with impaired testicular
      function.

      BACKGROUND AND HYPOTHESES

      The Department for Growth and Reproduction has helped to uncover the rising occurrence of
      early puberty, infertility, polycystic ovarian syndrome and testicular cancer that is
      worryingly high in large numbers parts of the world (1). These conditions are all governed by
      the hormonal axis that contains hypothalamus, pituitary gland, and the HPG axis (2). Our
      hypothesis is, that hCG may be a new regulator of calcium balance. hCG acts like luteinizing
      hormone (LH) produced by the pituitary gland and stimulates by binding to the LH receptor
      (LHCGR) production of testosterone in the testicles (3-6). we and others have found that that
      LHCGR is also located in other tissues than the gonad (7) and we suggest that LH stimulation
      probably also regulates calcium handling in the kidney. We have observed changes in serum
      calcium after hCG injection in patients with impaired testicular function, which indicates
      that the gonads and gonadotropins may be important for calcium and phosphate homeostasis. It
      is compatible with the fact that it has been shown that ex FSH can regulate bone function
      (8),and sex hormones are important for calcium absorption and excretion in the kidney (9-11).
      The latter is interesting because our research suggests that the receptor for the luteinizing
      hormone and hCG (LHCGR) plays an important role in the kidney, thus enabling a direct effect
      on calcium and phosphate handling for LHCGR agonists such as LH and hCG.

      With this study we want to investigate how hCG influences calcium homeostasis and
      subsequently other extragonadal organs by analyzing serum and urine from men with normal and
      impaired gonadal function

      DESIGN This is a prospective intervention study in cases and controls

      Patients and methods 10-15 men referred for hCG stimulation test due to suspected gonadal
      insufficiency after curative treatment for testicular cancer with orchiectomy, irradiation or
      chemotherapy age 18-80 years at Department of growth and reproduction, Rigshospitalet and
      10-15 men with normal reproductive function

      SAMPLE SIZE CALCULATION AND STATISTICS By using a test level of 5% (level of significance),
      power of 80% and at least 10 normal men and 10 men with impaired gonadal function completing
      the trial will enable us to detect a change in serum calcium of 6%, PTH of 25% and a change
      in serum Phosphate of 15%.

      SCREENING AND TIME COURSE Men referred for hCG stimulation test at our Department will be
      screened for eligibility to the study. Those who meet the criteria for participation will be
      informed, and if they consent allocated to the study.

      Each person will have one blood sampling performed.Venus blood is drawn before hCG
      administration, 2,8,24 72 and 120 hours after injection. Spot urine samples will be delivered
      and ECG monitoring will be performed at all time points. All men will be fasting for
      baseline, 2 hours, 24, 72 and 120 hours sampling. Serum will be send for analysis within 40
      minutes and the rest frozen within 1 hour and will be stored at minus 80 degrees celsius
      until analysis.

      Biostatistical analysis each individual's samples will be normalized by division of the value
      of the given parameter (for instance calcium or phosphate) to the baseline samples drawn
      before the intervention.

      Hence, samples from each volunteer at the different timepoints will be normalized with the
      individual's own baseline values before the administration of hCG. Initially, paired Student
      t tests will be used to compare changes in serum or urine by comparing baseline levels with
      the different time points. Unpaired Student t tests will be used to compare controls and men
      with gonadal insufficiency at all time points. Moreover, the presumable effect of multiple
      testing will be tested afterwards by using ANOVA followed by a post hoc Dunnett's /SIDAK
      multiple comparison test. All data will after indexation to baseline levels be shown as mean
      ± SEM. Differences were considered statistically significant when P ≤ 0.05.

      Predefined subgroups Changes in calcium and phosphate will be analyzed according to baseline
      sex steroids and delta sex steroids, LHCGR, BMI, GFR, PTH

      Principal Investigator: Li Juel Mortensen Sponsor: Martin Blomberg Jensen
    

Intervention name(s): human chorionic gonadotropin
Intervention type(s): Drug
Intervention description(s): a single injection of a standard dose
Intervention MeSH terms: Chorionic Gonadotropin
Intervention model: Single Group Assignment
Intervention model description: simple one arm intervention study
Masking: None (Open Label)
Primary purpose: Basic Science