Hormonal

Last year marked the fifty-year anniversary of the female birth control pill, making its debut in 1960 and it is now a multibillion dollar worldwide industry. With there being such a large market for contraceptives, then why don’t we see anything available for men? It turns out that this has been a slightly more difficult problem to tackle for the male system. This is due in part because of the enormous amount of sperm production, which is over 1000/second!1 Researchers around the world are currently studying different methods for male hormonal contraception that are as safe, effective, and have a similarly easy administration as the respective female hormonal contraceptives.

How does it work?

In a normal male, semen contains around 15 million sperm per mL.2 The goal of male hormonal contraception is to vastly reduce this number, creating a condition called azoospermia or oligospermia. Azoospermia is the complete lack of sperm in ejaculate, while oligospermia is a drastic reduction the concentration of sperm in the ejaculate. While azoospermia is the ultimate goal of male hormonal contraception, it is extremely difficult to achieve. However, conditions of “severe oligospermia” have been deemed acceptable, resulting in a pregnancy rate of about 1% per year.3

How can hormones be used to decrease sperm number?

There is a delicate balance in the body of several hormones that regulate spermatogenesis, including testosterone, gonadotropin releasing hormone (GnRH), follicle stimulating hormone (FSH), and luteinizing hormone (LH). In a normal male GnRH is released in a pulsatile fashion from the hypothalamus and travels via the hypothalamo-hypophysial portal system, where it exerts its effect on the adenohypophysis or anterior pituitary. The adenohypophysis is composed of glandular cells, which under stimulation from GnRH secrete FSH and LH. The LH in turn stimulates Leydig cells in the testicles to synthesize and secrete testosterone. Testosterone is released into the seminiferous tubules of the sperm as well as into systemic circulation, where it exerts a negative feedback function on the hypothalamus and adenohypophysis, thereby inhibiting the release of GnRH, FSH and LH. Full sperm maturation relies on the presence of testosterone, FSH and LH, with each stimulating different processes of maturation. However, the exact effect and mechanism of each of these hormones on spermatogenesis is not known.

Male hormonal contraceptives utilize the negative feedback system of testosterone on the levels of GnRH, FSH and LH. By introducing exogenous sources of testosterone the testicles are deprived of the signals needed for proper sperm maturation.

Fig 1

Early studies of the effectiveness of exogenous testosterone were conducted by the World Health Organization as a weekly intramuscular injection of a testosterone analogue, testosterone enanthate. Testosterone alone was shown to be an effective contraceptive method with nearly a 95% efficacy.5 However, this method was not very practical, requiring a weekly visit to a doctor for administration of an uncomfortable intramuscular injection and improved methods were needed.

Testosterone Undecanoate

More recently studies have considered a longer-lasting injection of testosterone in the form of testosterone undecanoate (TU) alone and its possible use in creating azoospermia or oligospermia. The first studies of such a contraceptive method were conducted on 308 healthy Chinese men, with an initial intramuscular loading dose of TU of 1000mg followed by monthly doses of 500mg (maximum of six injections) until either azoospermia or severe oligospermia were produced.6 The results of this study showed a very high efficacy rate with only 9 of the 308 volunteers not responding to the treatment. Of the remaining participants 296 responded, there were no pregnancies reported, while all men returned to normal levels of spermatogenesis within the allotted 12 month recovery period.6 A larger and longer study using only TU as a contraceptive was also conducted on 1045 Chinese men over a 30 month period and showed a similar efficacy rate of about 95%.7­

Testosterone and Progestins

Exogenous testosterone alone was able to suppress sperm count in many subjects, but a search for alternatives show that a mixture of testosterone and progesterone derivatives to be even more efficient. Recent studies were conducted with etonogestrel (ENG) implant in combination with TU injections.9 In this trial, 354 men were tested and given either a high dose or low dose implant along with TU injections or given placebos. The high-release group showed 94% of the men had sperm count reduced to less than 1 million/mL. It is also believed that altering the dosing of one or both may increase the efficacy.

More recent studies have looked at using a combination of TU with norethisterone enanthate (NETE) and depot medroxyprogesterone acetate (DMPA). A study on a combination therapy was conducted using different doses of TU alone or with DMPA at different doses. All but two of the 30 men in the study showed azoospermia or severe oligospermia, while everyone who received the combination of TU and DMPA, regardless of the dose, were effectively suppressed to azoospermia.10

What does the Future Hold?

Development of new variations on testosterone is revealing alternatives that may be able to act as a single-agent contraceptive with high efficacy and possibly the ability to be taken orally. One such new testosterone that is still in the early stages of testing is Dimethandrolone undecanoate (DMAU), which has shown to be a potent androgen, but also has the ability to bind to progestin receptors. Currently, tests with this compound are being conducted on rats, but its dual androgen/progestin activities show great promise.12

Another emerging field of study for contraceptives does not use steroid hormones directly. This class of molecules is referred to as nonsteroidal selective androgen receptor modulators (SARMs). It is hoped that further research of these modulators whose selectivity can be induced for the hypothalamus and pituitary. A study using SARMs showed suppression of sperm by 75% in rats and it is hoped that by avoiding use of steroids some side effects associated with them can be avoided.13

Side Effects

There is a wide range of side effects with using any of the aformentioned methods which are typical of an increase in circulating androgens in the system. Some of the minor side effects are an increase in lean muscle mass, acne, weight gain, mood change, reduce libido and hair loss. Hopefully, with further research and experimentation some of these side effects can be reduced or eliminated completely. However, the two most concerning side effects of increasing androgen levels are prostate growth and decrease in high density lipid cholesterol levels (HDL-C). These cholesterols are thought to decrease the risk of atherosclerosis but HDL-C levels of subjects in clinical trials have shown up to a 15% decrease.14 While other research has shown that exogenous testosterone has no significant impact on prostate size or PSA levels.15

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