ENDOCRINE APPROACH TO MALE CONTRACEPTION

Part of “CHAPTER 123 – MALE CONTRACEPTION“

The administration of testosterone (T) to normal men functions as a contraceptive by suppressing secretion of the pituitary gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) (see Chap. 119). Low levels of LH and FSH deprive developing sperm of the signals required for normal maturation, leading to reversible infertility in most, but not all, men. In the normal male, FSH acts on Sertoli cells in the seminiferous tubules of the testis to facilitate sperm maturation. The absence of FSH, or blockade of the FSH receptor, has a deleterious effect on sperm counts, but mature sperm capable of fertilization persist.3 LH stimulates the production of T by Leydig cells in the testis. Blockade of LH production shuts down the testicular production of T and leads to the cessation of sperm production; however, the absence of T is harmful since T is necessary to maintain normal male health.

Therefore, attempts at the formulation of a hormonal contraceptive must (a) contain some androgen activity to prevent hypogonadism and (b) suppress LH and FSH levels low enough to block spermatogenesis. T alone accomplishes both goals, but, nevertheless, some men remain fertile on contraceptive regimens using only T. Compounds such as gonadotropin-releasing hormone (GnRH) analogs or progestins that synergistically suppress pituitary gonadotropin production or directly block sperm production have, therefore, been combined with T in attempts to optimize its contraceptive efficacy further.

TESTOSTERONE CONTRACEPTIVE TRIALS: GENERAL CONSIDERATIONS

In assessing the efficacy of potential male contraceptives, it is important to determine what level of sperm inhibition is necessary to achieve infertility; however, this is not precisely known. Sperm counts in normal men vary from 20 to 200 million sperm per milliliter of ejaculate. The absence of spermatozoa in the ejaculate, a condition termed azoospermia, renders fertilization impossible and is, therefore, the ultimate goal of male contraception. Unfortunately, azoospermia has not been achieved reliably in all men in studies using existing hormonal techniques. Most studies have some subjects who sustain partial but incomplete reduction of their sperm counts, a condition called oligozoospermia. There is good evidence that sperm counts <3 million sperm per milliliter of ejaculate are associated with decreased rates of pregnancy.4 This “severe oligozo-ospermia” decreases the chances of conception considerably, and is considered a reasonable short-term goal for male contraceptive research.

Additional factors important in the design of a hormonal contraceptive include time until onset of action and method of administration. Most hormonal contraceptives do not incapacitate existing sperm; they block sperm production. Since sperm take an average of 72 days to reach maturity, it is likely that any contraceptive based on manipulation of the hormonal axis will be associated with some delay in the onset of full contraceptive efficacy. In addition, it is important to consider ethnic differences in interpreting results of contraceptive trials. Study volunteers in Asia are more susceptible to T-induced suppression of spermatogenesis than are men studied in Europe, North America, and Australia.4,5 While the reason for this difference remains to be elucidated, it is important in the interpretation of trial results and complicates extrapolation of data to different populations.

THE CONTRACEPTIVE ANDROGEN

Administration of native T is impractical because when given orally or by injection it is promptly degraded by the liver. In addition, many orally active androgens (those with a 17-ethinyl group) can cause liver damage and are, therefore, not considered safe for long-term use in oral contraceptives.6 Most current regimens use T esters such as T enanthate (TE), given by intramuscular (im) injection on a weekly to fortnightly basis.

Other methods of sustained delivery for T that are suitable for use in a contraceptive regimen are being examined. T buciclate, a synthetic ester given by depot injection, maintains physiologic androgen levels for up to 3 months in hypogonadal men.7 T undecanoate (TU), an ester that is absorbed via lymphatics and therefore escapes first-pass hepatic metabolism,8 can be given orally twice a day; it can also be used by injection where it maintains serum T levels for at least 6 weeks in hypogonadal men.9 In addition, research into injectable steroid polymer microparticles or fused crystalline T implants reveals a similar ability to maintain T levels in hypogonadal men.10,11 and 12

Other esters such as 19-nortestosterone (19-NT) have been evaluated as potential substitutes for TE. In addition to its potent androgen effects, 19-NT has ten times the progestational activity of T and therefore inhibits FSH and LH production to a greater degree than TE.13

A derivative of 19-NT, 7α-methyl-19-nortestosterone (MENT), is also of interest. The 7-methylation of this compound prevents 5α-reduction, thus preventing its dihydrotestosterone (DHT)-like effects.14 This is of particular importance in spermatogenesis, as it has been shown that men who remain oligospermic after TE administration have higher DHT levels.15 To date, 5-MENT has not been used in contraceptive trials, but seems a likely candidate for future studies.

CONTRACEPTIVE TRIALS: I. TESTOSTERONE ALONE

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