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Overlapping dose responses of spermatogenic and extragonadal testosterone actions jeopardize the principle of hormonal male contraception.

ABSTRACT: Testosterone (T), alone or in combination with progestin, provides a promising approach to hormonal male contraception. Its principle relies on enhanced negative feedback of exogenous T to suppress gonadotropins, thereby blocking the testicular T production needed for spermatogenesis, while simultaneously maintaining the extragonadal androgen actions, such as potency and libido, to avoid hypogonadism. A serious drawback of the treatment is that a significant proportion of men do not reach azoospermia or severe oligozoospermia, commensurate with contraceptive efficacy. We tested here, using hypogonadal luteinizing hormone/choriongonadotropin receptor (LHCGR) knockout (LHR(-/-)) mice, the basic principle of the T-based male contraceptive method, that a specific T dose could maintain extragonadal androgen actions without simultaneously activating spermatogenesis. LHR(-/-) mice were treated with increasing T doses, and the responses of their spermatogenesis and extragonadal androgen actions (including gonadotropin suppression and sexual behavior) were assessed. Conspicuously, all dose responses to T were practically superimposable, and no dose of T could be defined that would maintain sexual function and suppress gonadotropins without simultaneously activating spermatogenesis. This finding, never addressed in clinical contraceptive trials, is not unexpected in light of the same androgen receptor mediating androgen actions in all organs. When extrapolated to humans, our findings may jeopardize the current approach to hormonal male contraception and call for more effective means of inhibiting intratesticular T production or action, to achieve consistent spermatogenic suppression.

SUBMITTER: Oduwole OO

PROVIDER: S-EPMC4376501 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Overlapping dose responses of spermatogenic and extragonadal testosterone actions jeopardize the principle of hormonal male contraception.

Oduwole Olayiwola O OO Vydra Natalia N Wood Nicholas E M NE Samanta Luna L Owen Laura L Keevil Brian B Donaldson Mandy M Naresh Kikkeri K Huhtaniemi Ilpo T IT

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20140305 6

Testosterone (T), alone or in combination with progestin, provides a promising approach to hormonal male contraception. Its principle relies on enhanced negative feedback of exogenous T to suppress gonadotropins, thereby blocking the testicular T production needed for spermatogenesis, while simultaneously maintaining the extragonadal androgen actions, such as potency and libido, to avoid hypogonadism. A serious drawback of the treatment is that a significant proportion of men do not reach azoosp ...[more]

PMID: 24599970

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Project description:ContextMale hormonal contraception (MHC) combines hypothalamic-pituitary-gonadal axis blockade with exogenous androgen delivery to maintain extragonadal androgen end-organ effects. Concern exists that MHC may adversely impact prostate health.ObjectiveThe objective of the study was to determine the molecular impact of MHC on intraprostatic androgen concentrations and androgen action.DesignThis was a single-blind, randomized, placebo-controlled study.SettingThe study was conducted at an academic medical center.Participants32 healthy men aged 25-55 yr participated in the study.InterventionInterventions included placebo, daily transdermal testosterone (T) (T-gel), T-gel + depomedroxyprogesterone acetate (T+DMPA), or T-gel + dutasteride daily (T+D) for 12 wk, and prostate biopsy during treatment wk 10.Main outcome measuresSerum and prostate androgen concentrations and prostate epithelial-cell gene expression were measured.ResultsThirty men completed the study. Serum T levels were significantly increased in T-gel and T+D groups compared with baseline (P < 0.05) but were decreased with the addition of DMPA. Intraprostatic androgens were no different from placebo with T-gel treatment. Addition of DMPA to T resulted in 40% lower intraprostatic dihydrotestosterone (DHT) concentration (P = 0.0273 vs. placebo), whereas combining dutasteride with T resulted in a 90% decrease in intraprostatic DHT (P = 0.0012), 11-fold increased intraprostatic T (P = 0.0011), and 7-fold increased intraprostatic androstenedione (P = 0.0011). Significant differences in global or androgen-regulated prostate epithelial-cell gene expression were not observed. Androgen-regulated gene expression correlated with epithelial-cell androgen receptor and prostatic DHT in placebo, T-gel, and T+DMPA arms and with T and androstenedione levels in the T+D arm.ConclusionsMHC regimens do not markedly alter gene expression in benign prostate epithelium, suggesting they may not alter risk of prostate disease. Longer-term studies examining the impact of MHC on prostate health are needed.

Project description:Importance:Since 2016, 11 states have expanded the scope of pharmacists to include direct prescription of hormonal contraception. Dispensing greater than 1 month's supply is associated with improved contraceptive continuation rates and fewer breaks in coverage. Scant data exist on the practice of pharmacist prescription of contraception and its outcomes compared with traditional, clinic-based prescriptions. Objective:To compare the amount of hormonal contraceptive supply dispensed between pharmacists and clinic-based prescriptions. Prescribing patterns were assessed by describing prescribing practices for women with contraindications to combined hormonal contraception. Characteristics of women seeking hormonal contraception directly from pharmacists were also described. Design, Setting, and Participants:This cohort study surveyed women aged 18 to 50 years who presented to pharmacies in California, Colorado, Hawaii, and Oregon for hormonal contraception prescribed by a clinician or a pharmacist between January 30 and November 1, 2019. Exposures:Pharmacist or clinic-based prescription of contraception. Main Outcomes and Measures:Months of contraceptive supply dispensed. Results:Four hundred ten women (mean [SD] age, 27.1 [7.7] years) were recruited who obtained contraception directly from a pharmacist (n?=?144) or by traditional clinician prescription (n?=?266). Women obtaining contraception from a pharmacist were significantly younger (82 [56.9%] vs 115 [43.2%] participants aged 18-24 years; P?=?.03), had less education (38 [26.4%] vs 100 [37.6%] with a bachelor degree; P?=?.002), and were more likely to be uninsured (16 [11.1%] vs 8 [3.0%] participants; P?=?.001) compared with women with a prescription from a clinician. Pharmacists were significantly more likely to prescribe a 6-month or greater supply of contraceptives than clinicians (6.9% vs 1.5%, P?<?.001) and significantly less likely to only prescribe a 1-month supply (42 [29.2%] vs 118 [44.4%] prescriptions; P?<?.001). Controlling for all covariates, women seen by pharmacists had higher odds of receipt of a 6-month or greater supply of contraceptives compared with those seen by clinicians (odds ratio?=?3.55; 95% CI, 1.88-6.70). Pharmacists were as likely as clinicians to prescribe a progestin-only method to women with a potential contraindication to estrogen (n?=?60 women; 8 [20.0%] vs 6 [30.0%], P?=?.52). Conclusions and Relevance:These findings suggest that pharmacist prescription of contraception may be associated with improved contraceptive continuation by preventing breaks in coverage through the provision of a greater supply of medication. Efforts are needed to educate prescribing providers on the importance of dispensing 6 months or greater contraceptive supply.

Project description:ObjectivesNew Mexico is a large rural state with high rates of unintended pregnancy and limited access to contraception. In 2017, the New Mexico Pharmacist Prescriptive Authority Act was amended to allow pharmacists to prescribe hormonal contraception. We explored pharmacist perspectives on prescribing hormonal contraceptives, including perceived barriers and facilitators to implementation in rural New Mexico and opinions on over-the-counter (OTC) access, and prescribing and inserting subdermal contraceptive implants.MethodsThis qualitative study recruited rural pharmacists using contact information from the New Mexico Board of Pharmacy and at a state-level pharmacist conference. We conducted semistructured telephone interviews with pharmacists focusing on benefits and concerns about prescribing hormonal contraception, resources required, perspectives on OTC access, and interest in prescribing and placing contraceptive implants. Deidentified transcribed interviews were analyzed by 2 independent coders for emerging themes.ResultsFrom November 2017 to January 2018, we recruited 25 rural pharmacists and conducted 21 interviews. The majority of participants were male (71%), aged over 60 years (43%), and in practice for over 20 years (52%). Interviewees were mostly positive about prescribing hormonal contraception citing community benefits. The top 3 perceived barriers were training needs, reimbursement, and liability. The top 3 facilitators were the availability of private areas within pharmacies, pharmacists' role as knowledgeable health care team members, and pharmacist accessibility without appointments. Most pharmacists did not support OTC access to hormonal contraception, and over half were interested in certification to prescribe and place subdermal contraceptive implants.ConclusionNew Mexico pharmacists identified community benefits of pharmacy access to hormonal contraception and were interested in training. Several barriers must be addressed to realize the potential of this practice expansion.

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Overlapping dose responses of spermatogenic and extragonadal testosterone actions jeopardize the principle of hormonal male contraception.

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Overlapping dose responses of spermatogenic and extragonadal testosterone actions jeopardize the principle of hormonal male contraception.

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