Human Growth Hormone Pre-treatment for 6 Weeks Prior to Ovulation Induction for IVF

NCT ID: NCT02179255

Last Updated: 2020-02-18

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

UNKNOWN

Clinical Phase

PHASE1/PHASE2

Total Enrollment

30 participants

Study Classification

INTERVENTIONAL

Study Start Date

2014-08-01

Study Completion Date

2022-06-30

Brief Summary

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Synthetic human growth hormone (HGH) has been available for more than a decade for specific indication in children and adults. Past Randomized Control Trials (RCT)s of HGH (under off-label use) for improving ovarian function have shown that a combination of traditional gonadotropin ovulation induction protocols, with addition of HGH is effective in increasing pregnancy rates, but not increasing egg production after IVF in women with documented diminished ovarian reserve (DOR). The investigators hypothesize that by initiating HGH at least 6 weeks prior to IVF start, the investigators will be able to increase production of oocytes and further improve pregnancy chances. This hypothesis is based on prior observations of effects of growth hormone on small antral follicles and the fact that prior studies utilized HGH principally only during ovulation induction itself.

The investigators plan to recruit 30 women (15 in each group) to an open label randomized controlled trial of HGH for augmentation of ovarian response among women with documented DOR and poor prior response to ovulation induction.

Eligible participants will be women \< 45 years with documented history of prior retrieval of 2 or fewer oocytes while on maximal ovulation induction despite prior supplementation with dehydroepiandrosterone (DHEA).

Women will be treated with 1.9 mg (5.7 units) of HGH per day, beginning about 6 weeks before start of their treatment cycle. Cost of treatment with HGH will be a cost to the participating patient. HGH will cost the patient approximately $800 per week of treatment. Patients who are randomized to the non-HGH treated group, and do not conceive, will in the following cycle be offered HGH supplementation outside of this clinical trial. This subsequent cycle will not be part of the study dataset and patients will also be responsible for the cost of HGH.

Even with only 7 patients in each group, this trial will have a 99% power (error 0.05%) to detect a mean increase to 4 oocytes in the treated group. The investigators plan to recruit 15 patients in each group to allow for possible dropouts.

Detailed Description

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Synthetic HGH was developed in 1985 and approved by the FDA for specific uses in children and adults (1996; 2003). In children, HGH injections are approved for treating short stature of unknown cause as well as poor growth due to a number of medical causes, including:

* Turner's syndrome, a genetic disorder that affects a girl's development.
* Prader-Willi syndrome, an uncommon genetic disorder causing poor muscle tone, low levels of sex hormones, and a constant feeling of hunger.
* Chronic kidney insufficiency.
* HGH deficiency or insufficiency.
* Children born small for gestational age.

In adults, approved uses of HGH include:

* Short bowel syndrome, a condition in which nutrients are not properly absorbed due to severe intestinal disease or the surgical removal of a large portion of the small intestine.
* HGH deficiency due to rare pituitary tumors or their treatment.
* Muscle-wasting disease associated with HIV/AIDS.

HGH supplementation is potentially useful in ovulation induction. Over the last decade, as recombinant HGH has become commercially available, there have been many studies looking at the effects of HGH on ovulation induction. Almost all of these studies administered HGH along with routine fertility medication during the ovulation induction cycle. Most studies used HGH doses between 4 units and 12 Units. A few studies started GH on day 21 of the previous cycle.

A recent Cochrane review found that, while HGH did not improve results in routine IVF cycles there is "some evidence of increased pregnancy and birth rates in women who are considered 'poor responders' to in vitro fertilization."

HGH is reported to modulate the action of follicle stimulating hormone (FSH) on follicles by up-regulating local synthesis of IGF-1. A similar effect was, interestingly, noted by Casson et al. (Casson, Santoro et al. 1998; Casson, Lindsay et al. 2000) in early experiments using DHEA with treated patients having increased IGF-1. Much of the focus on gonadotropin /IGF-1

interaction has revolved around the effects on granulosa cell cultures to increase aromatase activity, estradiol production progesterone production and Luteinizing Hormone (LH) receptor formation. However,Insulin-Like Growth Factor-1 (IGF-1) also has a proposed role in stimulating early follicle development and oocyte maturation (Yoshimura, Ando et al. 1996; Yoshimura, Aoki et al. 1996).

Based on these observations, we believe that HGH in past trials has not been used to maximal effect. Since HGH, like DHEA, appears to affect small growing follicles, weeks to months removed from gonadotropin sensitivity, the greatest potential for HGH, under our hypothesis, would be its use, attempting to affect these small growing follicles. In analogy to DHEA supplementation, this would mean that HGH supplementation would have to be initiated at least 6 weeks prior to IVF cycle stimulation start. Theoretically, administration of HGH during the 6 week before starting an IVF cycle will have an effect on developing antral follicles to present a larger and better quality cohort of follicles when ovulation induction is begun.

Conditions

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Female Infertility Due to Diminished Ovarian Reserve

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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Human Growth Hormone

1.9 mg (5.7 units) daily injection of Recombinant Human Growth Hormone (HGH) for at least 6 weeks (42 days) plus FSH 450 to 600 units per day administered subcutaneous (SQ) daily dose adjusted based on the patients response starting on day 2 of the 28 day menstrual cycle and continued until Ovulation trigger

Group Type EXPERIMENTAL

Human Growth Hormone

Intervention Type DRUG

1.9 mg (5.7 units) daily injection of Recombinant Human Growth Hormone (HGH) for at least 6 weeks (42 days) continuing into the approximately 14 days of ovulation induction phase of the trial.

Follicle Stimulating Hormone

Intervention Type DRUG

FSH 450 to 600 units per day administered SQ daily dose adjusted based on the patients response starting on day 2 of the 28 day menstrual cycle and continued until Ovulation trigger

Follicle Stimulating Hormone

FSH 450 to 600 units per day administered SQ daily dose adjusted based on the patients response starting on day 2 of the 28 day menstrual cycle and continued until Ovulation trigger

Group Type ACTIVE_COMPARATOR

Follicle Stimulating Hormone

Intervention Type DRUG

FSH 450 to 600 units per day administered SQ daily dose adjusted based on the patients response starting on day 2 of the 28 day menstrual cycle and continued until Ovulation trigger

Interventions

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Human Growth Hormone

1.9 mg (5.7 units) daily injection of Recombinant Human Growth Hormone (HGH) for at least 6 weeks (42 days) continuing into the approximately 14 days of ovulation induction phase of the trial.

Intervention Type DRUG

Follicle Stimulating Hormone

FSH 450 to 600 units per day administered SQ daily dose adjusted based on the patients response starting on day 2 of the 28 day menstrual cycle and continued until Ovulation trigger

Intervention Type DRUG

Other Intervention Names

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Human Growth Hormone (HGH) Somatotropin Omnitrope Norditropin Humatrope Saizen Genotropin Serostim Nutropin Tev-tropin Zorbtive Bravelle Follistim Gonal-F Menopure

Eligibility Criteria

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Inclusion Criteria

* The study will be limited to women with Poor Response to prior treatment with evidence of diminished ovarian reserve with 2 or fewer oocytes in a previous ovulation induction cycles with maximal gonadotrophin stimulation. All women in this study will be \<45 years old.

Exclusion Criteria

* Cardiac disease, evidence of glucose intolerance
Minimum Eligible Age

18 Years

Maximum Eligible Age

44 Years

Eligible Sex

FEMALE

Accepts Healthy Volunteers

No

Sponsors

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Center for Human Reproduction

OTHER

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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David H Barad, MD

Role: PRINCIPAL_INVESTIGATOR

Center for Human Reproduction

Norbert Gleicher

Role: STUDY_CHAIR

Center for Human Reproduction

Locations

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Center for Human Reproduction

New York, New York, United States

Site Status

Countries

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United States

References

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FDA approves human growth hormone for wasting syndrome. AIDS Patient Care STDS. 1996 Dec;10(6):379-80. No abstract available.

Reference Type BACKGROUND
PMID: 11361571 (View on PubMed)

FDA approves growth hormone for short children. Child Health Alert. 2003 Sep;21:4. No abstract available.

Reference Type BACKGROUND
PMID: 14552287 (View on PubMed)

Bergh C, Hillensjo T, Wikland M, Nilsson L, Borg G, Hamberger L. Adjuvant growth hormone treatment during in vitro fertilization: a randomized, placebo-controlled study. Fertil Steril. 1994 Jul;62(1):113-20.

Reference Type BACKGROUND
PMID: 7516295 (View on PubMed)

Dor J, Seidman DS, Amudai E, Bider D, Levran D, Mashiach S. Adjuvant growth hormone therapy in poor responders to in-vitro fertilization: a prospective randomized placebo-controlled double-blind study. Hum Reprod. 1995 Jan;10(1):40-3. doi: 10.1093/humrep/10.1.40.

Reference Type BACKGROUND
PMID: 7745068 (View on PubMed)

Suikkari A, MacLachlan V, Koistinen R, Seppala M, Healy D. Double-blind placebo controlled study: human biosynthetic growth hormone for assisted reproductive technology. Fertil Steril. 1996 Apr;65(4):800-5. doi: 10.1016/s0015-0282(16)58217-x.

Reference Type BACKGROUND
PMID: 8654642 (View on PubMed)

Bergh C, Carlstrom K, Selleskog U, Hillensjo T. Effect of growth hormone on follicular fluid androgen levels in patients treated with gonadotropins before in vitro fertilization. Eur J Endocrinol. 1996 Feb;134(2):190-6. doi: 10.1530/eje.0.1340190.

Reference Type BACKGROUND
PMID: 8630518 (View on PubMed)

Casson PR, Lindsay MS, Pisarska MD, Carson SA, Buster JE. Dehydroepiandrosterone supplementation augments ovarian stimulation in poor responders: a case series. Hum Reprod. 2000 Oct;15(10):2129-32. doi: 10.1093/humrep/15.10.2129.

Reference Type BACKGROUND
PMID: 11006185 (View on PubMed)

Casson PR, Santoro N, Elkind-Hirsch K, Carson SA, Hornsby PJ, Abraham G, Buster JE. Postmenopausal dehydroepiandrosterone administration increases free insulin-like growth factor-I and decreases high-density lipoprotein: a six-month trial. Fertil Steril. 1998 Jul;70(1):107-10. doi: 10.1016/s0015-0282(98)00121-6.

Reference Type BACKGROUND
PMID: 9660430 (View on PubMed)

Hazout A, Junca Am, Menezo Y, Demouzon J, Cohen-Bacrie P. Effect of growth hormone on oocyte competence in patients with multiple IVF failures. Reprod Biomed Online. 2009 May;18(5):664-70. doi: 10.1016/s1472-6483(10)60011-9.

Reference Type BACKGROUND
PMID: 19549445 (View on PubMed)

Kucuk T, Kozinoglu H, Kaba A. Growth hormone co-treatment within a GnRH agonist long protocol in patients with poor ovarian response: a prospective, randomized, clinical trial. J Assist Reprod Genet. 2008 Apr;25(4):123-7. doi: 10.1007/s10815-008-9212-7.

Reference Type BACKGROUND
PMID: 18392675 (View on PubMed)

Owen EJ, Shoham Z, Mason BA, Ostergaard H, Jacobs HS. Cotreatment with growth hormone, after pituitary suppression, for ovarian stimulation in in vitro fertilization: a randomized, double-blind, placebo-control trial. Fertil Steril. 1991 Dec;56(6):1104-10. doi: 10.1016/s0015-0282(16)54724-4.

Reference Type BACKGROUND
PMID: 1743329 (View on PubMed)

Tesarik J, Hazout A, Mendoza C. Improvement of delivery and live birth rates after ICSI in women aged >40 years by ovarian co-stimulation with growth hormone. Hum Reprod. 2005 Sep;20(9):2536-41. doi: 10.1093/humrep/dei066. Epub 2005 Apr 28.

Reference Type BACKGROUND
PMID: 15860489 (View on PubMed)

Yoshimura Y, Ando M, Nagamatsu S, Iwashita M, Adachi T, Sueoka K, Miyazaki T, Kuji N, Tanaka M. Effects of insulin-like growth factor-I on follicle growth, oocyte maturation, and ovarian steroidogenesis and plasminogen activator activity in the rabbit. Biol Reprod. 1996 Jul;55(1):152-60. doi: 10.1095/biolreprod55.1.152.

Reference Type BACKGROUND
PMID: 8793070 (View on PubMed)

Demeestere I, Gervy C, Centner J, Devreker F, Englert Y, Delbaere A. Effect of insulin-like growth factor-I during preantral follicular culture on steroidogenesis, in vitro oocyte maturation, and embryo development in mice. Biol Reprod. 2004 Jun;70(6):1664-9. doi: 10.1095/biolreprod.103.023317. Epub 2004 Feb 11.

Reference Type BACKGROUND
PMID: 14960488 (View on PubMed)

Yoshimura Y, Aoki N, Sueoka K, Miyazaki T, Kuji N, Tanaka M, Kobayashi T. Interactions between insulin-like growth factor-I (IGF-I) and the renin-angiotensin system in follicular growth and ovulation. J Clin Invest. 1996 Jul 15;98(2):308-16. doi: 10.1172/JCI118794.

Reference Type BACKGROUND
PMID: 8755639 (View on PubMed)

Zhuang GL, Wong SX, Zhou CQ. [The effect of co-administration of low dosage growth hormone and gonadotropin for ovarian hyperstimulation in vitro fertilization and embryo transfer]. Zhonghua Fu Chan Ke Za Zhi. 1994 Aug;29(8):471-4, 510. Chinese.

Reference Type BACKGROUND
PMID: 7835118 (View on PubMed)

Sood A, Mohiyiddeen G, Ahmad G, Fitzgerald C, Watson A, Mohiyiddeen L. Growth hormone for in vitro fertilisation (IVF). Cochrane Database Syst Rev. 2021 Nov 22;11(11):CD000099. doi: 10.1002/14651858.CD000099.pub4.

Reference Type DERIVED
PMID: 34808697 (View on PubMed)

Other Identifiers

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04082014-02

Identifier Type: -

Identifier Source: org_study_id

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