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Hormone Secretion in Transgender Males

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ClinicalTrials.gov Identifier: NCT04321551
Recruitment Status : Not yet recruiting
First Posted : March 25, 2020
Last Update Posted : June 9, 2022
Sponsor:
Information provided by (Responsible Party):
Tracy Harrison, University of California, San Diego

Brief Summary:
Aim 1 utilizes prospective clinical studies in TGN to test the hypothesis that prolonged exogenous androgens alter menstrual cyclicity by inhibiting gonadotropin secretion, steroid hormone release, and ovulation. We will utilize a clinical trial of TRT to evaluate T suppression of ovarian follicle and hormone dynamics (Aim 1A) and LH pulsatility (Aim 1B).

Condition or disease Intervention/treatment Phase
Transgender Healthy Drug: Testosterone Cyp 200Mg/Ml Inj (in Oil) Drug: Letrozole Phase 4

Detailed Description:

We will conduct a prospective, controlled clinical trial of ovarian and menstrual cyclicity in TGN initiating TRT (Fig. 8). Enrollment will include 20 TGN and 20 cisgender female (CF) control subjects who report female gender identity congruent with female sex assignment at birth. All subjects will be age >18 y, with female sex assignment at birth, regular menstrual cycles, and body mass index 18-35 kg/m2. Subjects with history of prior T use, cancer, chemotherapy, or radiation of the brain, abdomen, or pelvis, current use of hormonal medications (including, but not limited to, metformin, insulin, progestins, or estrogenic medications), current endocrinopathy (including, but not limited to, PCOS, androgen secreting tumor, diabetes, or pituitary, thyroid, or adrenal disease), and renal, hepatic, cardiac, or hematologic disease will be excluded. TGN subjects will undergo baseline endocrine and menstrual cycle evaluation, followed by intramuscular (i.m.) administration of testosterone cypionate (TC) 50 mg (standard dose) every 7 d for 32 wks (Fig. 8). After 24 wks, an aromatase inhibitor, letrozole (LET, 2.5 mg/d oral), will be co-administered with TC for 8 wks to block estrogen synthesis and examine whether T's effects are independent of E2 signaling. TGN will collect first morning-voided urine daily at home for assessment of hormone levels during one complete menstrual cycle before TRT begins and continuing during TRT. Untreated CF controls will collect urine daily during one menstrual cycle. Urinary concentrations of LH, FSH, estrone (E1) conjugates, and pregnanediol glucuronide (PdG) will be measured via ELISA. Studies of steroidogenesis during the menopausal transition have demonstrated accuracy of monitoring urinary hormone metabolite levels to reconstruct ovarian cyclicity and ovulatory patterns170-173; we can use this methodology to track progression of any declining HPG axis output over time. All subjects will complete a daily uterine bleeding log using REDCap® and undergo weekly measurement of serum FSH, LH, E2, and P4 (ELISA), and T (LC-MS/MS) for confirmation of hormone dynamics demonstrated by urine hormone metabolite studies. TGN will also undergo weekly transvaginal ultrasound (US) using a 4- to 9-MHz probe to obtain three-dimensional (3D) pelvic imaging following initiation of TRT for confirmation of corpus luteum (CL) formation and regression analysis of hormone secretion patterns, endometrial thickness, antral follicle count (AFC), and volume of the uterus and ovaries. Changes in follicle dynamics will be studied with 3D US determination of the mean diameter of each antral in 1-mm increments from 2 to 9 mm, as in our prior reports174,175.

The primary endpoint will be Evidence of Luteal Activity (ELA), as defined by a 3-fold increase in urinary PdG level over baseline170,176. Basal urinary PdG levels, normalized to urinary creatinine excretion, will be determined based upon the minimum daily PdG level detected per cycle or 4-wk interval, as previously described170,176. Secondary endpoints will include mean serum FSH and LH levels, peak urinary LH concentration, and cumulative LH surge count. Follicular phase function will be defined per cycle (or per 4-wk interval in amenorrheic subjects) by creatinine-adjusted urinary E1 AUC. Five-day moving averages of creatinine-adjusted urinary FSH and LH levels will be calculated, with LH surge defined as a 3 standard deviation increase in the 5-d moving LH average, as previously described170,176. The proportion of subjects demonstrating an LH surge will be compared during successive 4-wk intervals.

We have already demonstrated successful recruitment and retention of TGN and CF participants in longitudinal studies involving daily urine collection and serial pelvic US (e.g., our study in Fig. 2 and others)174,175. TGN subjects will be serially evaluated for adverse effects of TRT per The Endocrine Society recommendations63. Details regarding safety monitoring are in the Human Subjects Section. We calculate that 15 subjects/group will have >95% power to detect a 30% decrease in the proportion of subjects with ELA at baseline compared to the final 4-week TC study interval (wks 21-24). Although we anticipate a larger, more clinically meaningful decrease, we have utilized a conservative target to maximize the study's power. Although we have had no dropouts in our current TGN pilot study, we factored a 20% dropout rate into our enrollment target of 20 subjects per group to ensure achieving sufficient power.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Other
Official Title: Clinical Trial of Androgen Effects on the Reproductive Neuroendocrine Axis
Estimated Study Start Date : July 1, 2023
Estimated Primary Completion Date : June 30, 2028
Estimated Study Completion Date : December 31, 2028

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Hormones

Arm Intervention/treatment
Experimental: Provocative Hormonal Testing
TGN subjects will undergo baseline endocrine and menstrual cycle evaluation, followed by intramuscular (i.m.) administration of testosterone cypionate (TC) 50 mg (standard dose) every 7 d for 32 wks (Fig. 8). After 24 wks, an aromatase inhibitor, letrozole (LET, 2.5 mg/d oral), will be co-administered with TC for 8 wks to block estrogen synthesis and examine whether T's effects are independent of E2 signaling.
Drug: Testosterone Cyp 200Mg/Ml Inj (in Oil)
Depo-Testosterone Injection, for intramuscular injection, contains testosterone cypionate which is the oil-soluble 17 (beta)- cyclopentylpropionate ester of the androgenic hormone testosterone. Testosterone cypionate is a white or creamy white crystalline powder, odorless or nearly so and stable in air. It is insoluble in water, freely soluble in alcohol, chloroform, dioxane, ether, and soluble in vegetable oils. The chemical name for testosterone cypionate is androst-4-en-3-one,17-(3-cyclopentyl-1- oxopropoxy)-, (17ß)-. Its molecular formula is C27H40O3, and the molecular weight 412.61.
Other Name: Depo-Testosterone

Drug: Letrozole
Letrozole is a nonsteroidal aromatase inhibitor (inhibitor of estrogen synthesis). It is chemically described as 4,4'-(1H-1,2,4-Triazol-1- ylmethylene)dibenzonitrile. Letrozole is a white to yellowish crystalline powder, practically odorless, freely soluble in dichloromethane, slightly soluble in ethanol, and practically insoluble in water. It has a molecular weight of 285.31, empirical formula C17H11N5, and a melting range of 184°C to 185°C. Letrozole is available as 2.5 mg tablets for oral administration.
Other Name: Femara




Primary Outcome Measures :
  1. Evidence of Luteal Activity [ Time Frame: Baseline, 12 weeks, 24 weeks, and 32 weeks ]
    The primary endpoint will be Evidence of Luteal Activity (ELA), as defined by a 3-fold increase in urinary pregnanediol glucuronide level over baseline.



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Ages Eligible for Study:   18 Years to 35 Years   (Adult)
Sexes Eligible for Study:   Female
Gender Based Eligibility:   Yes
Gender Eligibility Description:   Cisgender females Transgender males Gender non-binary individuals
Accepts Healthy Volunteers:   Yes
Criteria
  • Self-identified transgender or non-binary person assigned female at birth
  • No history of prior testosterone therapy
  • Regular menstrual cycles
  • Body mass index 18 - 35
  • Hemoglobin greater than than 11 gm/dl at screening evaluation
  • Presence of uterus and both ovaries at time of consent
  • Able to provide informed consent
  • No current endocrine disease- including, but not limited to, pituitary disease, adrenal disease, androgen secreting tumor, polycystic ovary syndrome, diabetes, or untreated thyroid disease.
  • Absence of cancer and any renal, hepatic, or cardiac disease
  • No current use of endocrine modulating medications (including, but not limited to, progestin therapy, estrogen containing medications, metformin, insulin)
  • No history of radiation or surgery involving brain, abdomen, or pelvis

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04321551


Contacts
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Contact: Tracy N Harrison, MD 858-822-1481 tnharrison@health.ucsd.edu
Contact: Eunice Tingzon 858-534-8930 etingzon@health.ucsd.edu

Sponsors and Collaborators
University of California, San Diego
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Responsible Party: Tracy Harrison, Professor of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Diego
ClinicalTrials.gov Identifier: NCT04321551    
Other Study ID Numbers: 200395
First Posted: March 25, 2020    Key Record Dates
Last Update Posted: June 9, 2022
Last Verified: June 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Tracy Harrison, University of California, San Diego:
Testosterone therapy
Additional relevant MeSH terms:
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Letrozole
Methyltestosterone
Testosterone
Testosterone undecanoate
Testosterone enanthate
Testosterone 17 beta-cypionate
Antineoplastic Agents
Aromatase Inhibitors
Steroid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Estrogen Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Androgens
Hormones
Antineoplastic Agents, Hormonal
Anabolic Agents