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.

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.

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