A detailed understanding of the hormonal regulation of spermatogenesis is required for the informed assessment and management of male fertility and, conversely, for the development of safe and reversible male hormonal contraception An approach to the study of these issues is outlined based on the use of well-defined in vivo models of gonadotropin/androgen deprivation and replacement, the quantitative assessment of germ cell number using stereological techniques, and the directed study of specific steps in spermatogenesis shown to be hormone dependent Drawing together data from rat, monkey, and human models, we identify differences between species and formulate an overview of the hormonal regulation of spermatogenesis There is good evidence for both separate and synergistic roles for both testosterone and follicle-stimulating hormone (FSH) in achieving quantitatively normal spermatogenesis Based on relatively selective withdrawal and replacement studies, FSH has key roles in the progression of type A to B spermatogonia and, in synergy with testosterone, in regulating germ cell viability Testosterone is an absolute requirement for spermatogenesis In rats, it has been shown to promote the adhesion of round spermatids to Sertoli cells, without which they are sloughed from the epithelium and spermatid elongation fails The release of mature elongated spermatids from the testis (spermiation) is also under FSH/testosterone control in rats Data from monkeys and men treated with steroidal contraceptives indicate that impairment of spermiation is a key to achieving azoospermia The contribution of 5alpha-reduced androgens in the testis to the regulation of spermatogenesis is also relevant, as 5alpha-reduced androgens are maintained during gonadotropin suppression and may act to maintain low levels of germ cell development These concepts are also discussed in the context of male hormonal contraceptive development

https://www.endocrine.org/~/media/endosociety/Files/EP/RPHR/57/RPHR_vol_57_ch_07_identification_of_specific_sites.pdf

Identification of specific sites of hormonal regulation in spermatogenesis in rats, monkeys, and man.

BACKGROUND: Following extensive research activity to develop an effective agent to control male fertility, such a product may be available for use within ,5 years. However, little is known concerning contraceptive knowledge, desires and attitudes of men in different countries, and their acceptance of male fertility control (MFC). METHODS: A survey of >9000 males aged 18 – 50 years was performed in nine countries on four continents in 2002. The objective was to compare, on a cross-cultural basis, the knowledge, attitudes and acceptability of MFC among men and assess their willingness to use such a method. RESULTS: Between 50 and 83% of the male respondents currently use contraceptive methods, and 55 – 81.5% reported that both partners participate in selecting the method of contraception employed. Overall acceptance of hormonal MFC was high (>55%), with 28.5– 71.4% of survey participants of various nationalities expressing the willingness to use such a method. CONCLUSION: While MFC appears to be well accepted overall, the willingness to use this type of contraception varies widely between differing population groups. The specific characteristics and profile of any MFC product will have to be carefully evaluated to accurately assess its acceptance, both by men and their female partners.

/pdf/attitudes-toward-male-fertility-control-results-of-a-3mmhur8jx1.pdf

Attitudes toward male fertility control: results of a multinational survey on four continents

The prospect of a hormonal male contraceptive is no longer distant. Data on the potential impact of this improvement in contraceptive provision, however, is limited, particularly between different cultures. We have therefore carried out a multi-centre study to assess men's attitudes to proposed novel hormonal methods. Questionnaire-based structured interviews were administered to men in Edinburgh, Cape Town, Shanghai and Hong Kong. Approximately 450 men were interviewed in Edinburgh, Shanghai and Hong Kong, and a slightly larger group (n = 493) in Cape Town to give samples (n > 150) of black, coloured and white men. Knowledge of existing male and female methods of contraception was high in all centres and groups. The majority of men welcomed a new hormonal method of contraception, 44-83% stating that they would use a male contraceptive pill. Overall, a pill was more acceptable than an injectable form (most popularly given at 3-6 month intervals); long-acting implants were least so except in Shanghai. Familiarity with comparable female methods appeared to influence acceptability, for both oral and injectable methods. Hong Kong was the only centre where a male method (condom) was currently the most commonly used; men there appeared to rate the convenience of condoms highly while being least likely to think that they provided effective protection against pregnancy compared to other centres, and were least enthusiastic about novel male methods. The acceptability of potential male hormonal methods of contraception was high in some groups but showed wide variability, determining factors including cultural background and current contraceptive usage. These results suggest that the emerging emphasis that men should have greater involvement in family planning will be substantiated when appropriate contraceptive methods become available.

Potential impact of hormonal male contraception: cross-cultural implications for development of novel preparations

Intratesticular testosterone (ITT) is thought to play a key role in the control of spermatogenesis in man but is rarely measured. The purposes of this study were 1) to examine the relationship between intratesticular fluid and serum testosterone (T) at baseline and during treatment with a contraceptive regimen known to suppress spermatogenesis and 2) to measure intratesticular fluid androgenic bioactivity. Seven men received 6 months of T enanthate (TE) 100 mg weekly intramuscularly plus levonorgestrel (LNG) 62.5 or 31.25 microg orally daily. Testicular fluid was obtained by percutaneous aspiration at baseline and during month 6. Mean luteinizing hormone (LH) was suppressed 98% from 3.79 +/- 0.80 IU/L at baseline to 0.08 +/- 0.03 IU/L. Mean follicle stimulating hormone (FSH) was suppressed 97%, from 3.29 +/- 0.67 IU/L to 0.10 +/- 0.03 IU/L. Mean serum T levels were similar before (22.8 +/- 1.9 nmol/L) and during treatment (28.7 +/- 2.0 nmol/L) (P = .12). ITT (822 +/- 136 nmol/L) was approximately 40x higher than serum T (P < .001) at baseline. ITT was suppressed 98% during treatment to 13.1 +/- 4.5 nmol/L, a level similar to baseline serum T (P = .08) but significantly lower than on-treatment serum T (P = .01). At baseline, intratesticular fluid androgenic bioactivity (583 +/- 145 nmol/L) was 70% of the ITT concentration measured by radioimmunoassay. Intratesticular androgenic bioactivity was suppressed 93% to 40 +/- 22 nmol/L (P < .01) during treatment, but was 3x higher than ITT (13.1 +/- 4.5 nmol/L). Sperm counts declined from 65 +/- 15 million/mL to 1.3 +/- 1.3 million/mL. In summary, TE plus LNG dramatically suppressed ITT (98%) and intratesticular androgenic bioactivity (93%) to levels approximating those in serum. ITT levels comparable with serum T were insufficient to support normal spermatogenesis. Intratesticular androgenic bioactivity was higher than ITT during treatment, suggesting that other androgens may be prevalent in the low-ITT environment.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/j.1939-4640.2004.tb03164.x

Intratesticular testosterone concentrations comparable with serum levels are not sufficient to maintain normal sperm production in men receiving a hormonal contraceptive regimen.

In previous studies of testicular biopsy tissue from healthy men, intratesticular testosterone (ITT) has been shown to be much higher than serum testosterone (T), suggesting that high ITT is needed relative to serum T for normal spermatogenesis in men. However, the quantitative relationship between ITT and spermatogenesis is not known. To begin to address this issue experimentally, we determined the dose-response relationship between human chorionic gonadotropin (hCG) and ITT to ascertain the minimum dose needed to maintain ITT in the normal range. Twenty-nine men with normal reproductive physiology were randomized to receive 200 mg T enanthate weekly in combination with either saline placebo or 125, 250, or 500 IU hCG every other day for 3 wk. ITT was assessed in testicular fluid obtained by percutaneous fine needle aspiration at baseline and at the end of treatment. Baseline serum T (14.1 nmol/liter) was 1.2% of ITT (1174 nmol/liter). LH and FSH were profoundly suppressed to 5% and 3% of baseline, respectively, and ITT was suppressed by 94% (1234 to 72 nmol/liter) in the T enanthate/placebo group. ITT increased linearly with increasing hCG dose (P < 0.001). Posttreatment ITT was 25% less than baseline in the 125 IU hCG group, 7% less than baseline in the 250 IU hCG group, and 26% greater than baseline in the 500 IU hCG group. These results demonstrate that relatively low dose hCG maintains ITT within the normal range in healthy men with gonadotropin suppression. Extensions of this study will allow determination of the ITT concentration threshold required to maintain spermatogenesis in man.

/pdf/low-dose-human-chorionic-gonadotropin-maintains-aluyltsu1s.pdf

Low-Dose Human Chorionic Gonadotropin Maintains Intratesticular Testosterone in Normal Men with Testosterone-Induced Gonadotropin Suppression

Testosterone enanthate (TE) administration is associated with a failure rate (3.4/100 person-years) considerably lower than that of other currently available reversible male contraceptive methods. However acceptability of this regimen is limited by the need for weekly injections the lack of complete azoospermia and the decrease in high-density lipoprotein (HDL)-cholesterol. Under investigation is the concurrent administration of a progestin that can act synergistically with TE in the suppression of gonadotropins. Because of the additive effects the dose of each steroid can be decreased minimizing androgen-related side effects. Third-generation progestins and hybrid progestins seem to offer the most potential for such an approach. In particular the combination of cyproterone acetate (CPA) and TE has been found to result in a rapid profound suppression of spermatogenesis without side effects through its ability to block both the follicle-stimulating hormone and androgen effects at the testis level. The anti-androgenic action of CPA is based on its ability to competitively inhibit the binding of testosterone and dehydrotestosterone to androgen receptors. The block of intratesticular testosterone effect by CPA is presumed to cause a decrease in cell-adhesion molecule concentrations and contribute to the premature sloughing of permatids from the seminiferous epithelium thereby resulting in the early disappearance of spermatozoa from the ejaculate. This regimen did not cause any changes in plasma HDL or other lipoproteins or affect liver function test results.

Progestin-androgen combination regimens for male contraception.

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Progestin-androgen combination regimens for male contraception.