COMMENTARY

Testosterone Gel in IVF

Peter Kovacs, MD, PhD

Disclosures

April 21, 2011

The Effect of Transdermal Testosterone Gel Pretreatment on Controlled Ovarian Stimulation and IVF Outcome in Low Responders

Kim CH, Howles CM, Lee HA
Fertil Steril. 2011;95:679-683

Background

At birth, 1-2 million follicles are present in the ovaries, and the number declines to 400,000-500,000 by menarche. The rate of follicle loss is genetically programmed at the individual level. As the size of the follicle pool decreases, ovarian cycles become increasingly irregular. When the number of follicles is down to a few thousand, cyclic ovarian activity ceases.

Ovarian function is needed for successful reproduction. When the size of the follicle pool is reduced, the chance for pregnancy is diminished significantly as well. Follicle growth occurs in waves, and it takes about 3 months for a follicle to reach the ovulatory stage. Pituitary gonadotropins play an increasingly important role in the last 2 weeks of this process. However, they do not influence the size of the pool that enters the final stages of development.[1] Women with diminished ovarian reserve typically have fewer follicles reaching this stage. These patients can be identified on the basis of certain laboratory markers, smaller ovaries with fewer follicles on ultrasound, and most importantly, by poor response to stimulation. The management of these patients is rather challenging. In vitro fertilization (IVF) works best when several eggs are collected and the embryos for transfer can be selected from a larger cohort of embryos. This study assessed whether using testosterone gel prestimulation has an impact on treatment outcome.

Study Summary

In a prospective randomized study, Kim, Howles, and Lee evaluated the effects of 12.5-mg testosterone gel pretreatment (for 21 days) prior to the start of stimulation. The testosterone gel pretreatment group and a control group both received 300 IU/day of follicle-stimulating hormone (FSH) in combination with a gonadotropin-releasing hormone antagonist for stimulation. Demographic and past infertility parameters were comparable.

Women in the testosterone pretreatment group required fewer days of stimulation and fewer ampules of gonadotropin. Cycle cancellation occurred with similar frequency. In the testosterone group, women produced more follicles and more oocytes were retrieved. The numbers of available embryos and good quality embryos also were higher. Endometrial thickness and the number of embryos transferred were the same in both groups. The implantation rate was higher in the testosterone group (14.3% vs 7.2%), and the clinical pregnancy rate per transfer was significantly higher as well (31.5% vs 15.1%). The difference in live birth rates reached borderline significance (27.3% vs 12.7%; P = .057). The investigators concluded that testosterone pretreatment may have a positive effect on stimulation and IVF treatment outcomes in poor responder patients.

Viewpoint

Ovarian activity is primarily under the control of pituitary FSH and luteinizing hormone (LH), but within the ovary, important paracrine and autocrine effects modify ovarian activity. The main target for FSH is the granulosa cell, whereas LH primarily interacts with theca cells. Androgens produced by the theca cells are converted to estrogen in the granulosa cells under the influence of FSH. However, androgens increase granulosa cell FSH receptor expression and antral follicle count.[2,3]

Promising results with an androgen supplement (DHEA [dehydroepiandrosterone]) in the care of poor responders undergoing IVF have been published.[4] Other studies assessed the use of LH prior to stimulation. LH stimulates theca cell androgen synthesis, and through paracrine effects, could augment granulosa cell activity as well as follicle count.[5,6]

Stimulation protocols designed for poor responders typically involve the use of high-dose gonadotropin. Although this may lead to fewer cancelled cycles and more oocytes, a clear clinical benefit (eg, more pregnancies) has not been reported yet. To meaningfully improve the results for poor responders, it is necessary to increase the size of the follicle pool entering the final stages of development. The modification of the local endocrine environment may have this effect as suggested by this and previous reports.[4,7]

Side effects must also be considered. They are mainly related to the androgenic activity and may affect the skin and lipid levels. For now, until more support accumulates for its beneficial effects as an experimental approach, the prestimulation use of androgens could be offered to patients who are poor responders.

Abstract

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