Gonadotropin Therapy in Idiopathic Hypogonadal Non-Obstructive (GTIHNO)

"Gonadotropin Therapy in Idiopathic Hypogonadal Non-Obstructive Azoospermia (APHRODITE Groups 3-4): A Multicenter Randomized Controlled Trial"

The goal of this clinical trial is to determine whether short-term gonadotropin therapy (hCG + FSH) can increase sperm availability for ICSI in men with idiopathic non-obstructive azoospermia (NOA) and hypogonadism. The main questions it aims to answer are:

Does hormonal optimization improve the likelihood of obtaining usable sperm (via ejaculate or micro-TESE) by Week 16? Does hormonal therapy reduce the need for micro-TESE or improve downstream embryological and clinical outcomes?

Because there is a comparison group, researchers will compare hCG + FSH hormonal therapy with standard-of-care (no gonadotropins) to see if hormonal optimization increases sperm retrieval success and decreases surgical reliance.

Participants will:

Undergo baseline hormonal and semen testing Be randomized to either hormonal therapy or standard-of-care If in the hormonal arm: receive hCG and FSH with monthly dose titration and aromatase inhibitors if indicated Provide semen samples at Weeks 12 and 16 Undergo micro-TESE if no ejaculated sperm are found (timing per protocol) Complete safety assessments and follow-up through Week 16

Study Overview

• Status: Not yet recruiting
• Conditions: APHRODITE Group
• Intervention / Treatment: Other: hCG + FSH therapy; Other: No intervention

• Study Type: Interventional
• Enrollment (Estimated): 860
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Vipin Chandra, DGO; Phone Number: 9567971239; Email: drvipinchandra@indiraivf.in

Study Locations

• India
  • Bihar
    • Patna, Bihar, India, 800014
      • Recruitment
      • Contact: Dayaniddhi Kumar, Ph D; Phone Number: 9011803606
  • Karnataka
    • Bangalore, Karnataka, India, 560041
      • Recruitment
      • Contact: Shyam Gupta, MD; Phone Number: 9899984791; Email: centerhead.bangalore@indiraivf.in
  • Maharashtra
    • Bhāndup, Maharashtra, India
      • Recruitment
      • Contact: Rinoy Shreedharan, MD; Phone Number: +917874071247
    • Pune, Maharashtra, India
      • Recruitment
      • Contact: Amol Lunkad, MD
  • National Capital Territory of Delhi
    • Delhi, National Capital Territory of Delhi, India
      • Recruitment
  • Rajasthan
    • Jaipur, Rajasthan, India
      • Recruitment
      • Contact: Tanu Batra, MD; Phone Number: 09567971239; Email: ifa@indiraivf.in
  • Uttar Pradesh
    • Allahābād, Uttar Pradesh, India
      • Recruitment
      • Contact: Anjali Gahlan, MS
    • Lucknow, Uttar Pradesh, India
      • Recruitment
      • Contact: Pawan Yadav, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

- Idiopathic NOA; hypogonadal (TT <350 ng/dL on two fasting morning tests); FSH ≥7.6 IU/L (APHRODITE Group 3: 7.6-12.0 IU/L; Group 4: >12.0 IU/L).

Exclusion Criteria:

cryptorchidism, chemo/radiation, genetic NOA (e.g., AZFa/complete AZFb), testicular trauma/torsion, post-orchitis. prior micro-TESE within 12 months; recent gonadotropin therapy (<6 months); uncontrolled endocrine disease; active malignancy; severe liver disease; polycythemia (Hct>50%); inability to comply. Varicocele>= Grade 3

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Standard of Care	Other: No intervention; Standard of Care
Experimental: hCG + FSH therapy	Other: hCG + FSH therapy; hCG + FSH therapy with monthly hormone-driven titration (hCG initial ~83 µg SC twice weekly; no preset min/max; target TT >350-900 ng/dL) + FSH 150 IU SC twice weekly (increase to 150 IU SC three times weekly if 'FSH reset' <1.5 IU/L); allow anastrozole 1 mg PO daily /letrozole 2.5 mg half tablet alternate day if T/E <10

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Success or Sperm Availability	Sperm Availability for ICSI was defined as the presence of viable sperm suitable for intracytoplasmic sperm injection (ICSI) at any time from randomization through Week 16. Sperm could be obtained either through ejaculate or via microsurgical testicular sperm extraction (micro-TESE). Assessment of sperm availability was performed by a centralized adjudication committee, which was blinded to treatment allocation to ensure objective and unbiased evaluation.	from randomization through Week 16 via ejaculate or micro-TESE

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Micro-TESE Sperm Retrieval Rate (SSR)	Whether sperm are retrieved during micro-TESE	The Micro-TESE Sperm Retrieval Rate (SSR) was assessed during the period from randomization through Week 16. The outcome was determined based on the availability of at least one viable sperm retrieved via microsurgical testicular sperm extraction (micro-
Need for Micro-TESE Surgery	Whether the participant requires micro-TESE	Up to Week 16
Safety / Harms	All adverse events (AE/SAE) related to treatment or procedure	Week 16
ICSI Fertilization Rate	% of injected oocytes that form normal 2PN embryos	Within the ICSI cycle ≈ Day 1-3 after ICSI
Blastulation Rate	% of embryos reaching blastocyst stage	Day 5-7 after fertilization
Blastocyst Quality	Grading of blastocysts based on standard morphology criteria	Day 5-7 after fertilization
Top-Quality Blastocyst Rate	% of "top-1 quality" blastocysts formed	Day 5-7 after fertilization
Clinical Pregnancy Rate	Presence of gestational sac with cardiac activity on ultrasound	≈ 6-8 weeks after embryo transfer
Miscarriage Rate	Pregnancy loss before 20 weeks	From pregnancy confirmation to 20 weeks gestation
Live Birth	Delivery of a live infant	Up to delivery (~9 months after embryo transfer)

Collaborators and Investigators

• Sponsor: Indira IVF Hospital Pvt Ltd

Publications and helpful links

General Publications

• Esteves SC, Yarali H, Vuong LN, Carvalho JF, Ozbek IY, Polat M, Le HL, Pham TD, Ho TM. Low Prognosis by the POSEIDON Criteria in Women Undergoing Assisted Reproductive Technology: A Multicenter and Multinational Prevalence Study of Over 13,000 Patients. Front Endocrinol (Lausanne). 2021 Mar 12;12:630550. doi: 10.3389/fendo.2021.630550. eCollection 2021.
• Esteves SC, Humaidan P, Ubaldi FM, Alviggi C, Antonio L, Barratt CLR, Behre HM, Jorgensen N, Pacey AA, Simoni M, Santi D. APHRODITE criteria: addressing male patients with hypogonadism and/or infertility owing to altered idiopathic testicular function. Reprod Biomed Online. 2024 Apr;48(4):103647. doi: 10.1016/j.rbmo.2023.103647. Epub 2023 Oct 29.

Study record dates

Study Major Dates

• Study Start (Estimated): July 17, 2026
• Primary Completion (Estimated): January 16, 2027
• Study Completion (Estimated): July 17, 2027

Study Registration Dates

• First Submitted: February 3, 2026
• First Submitted That Met QC Criteria: April 14, 2026
• First Posted (Actual): April 20, 2026

Study Record Updates

• Last Update Posted (Actual): April 20, 2026
• Last Update Submitted That Met QC Criteria: April 14, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Hypogonadism; Male infertility; Non-obstructive azoospermia (NOA); Idiopathic NOA
• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Endocrine System Diseases; Genital Diseases, Male; Male Urogenital Diseases; Gonadal Disorders; Infertility; Hypogonadism; Infertility, Male
• Other Study ID Numbers: IIHL-UDR-P-002-2025 (Other Identifier: Indira IVF Hospital Limited)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: will be shared on request

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No