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      Dose-dependent response to long-term clomiphene citrate in male functional hypogonadotropic hypogonadism


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          Functional hypogonadotropic hypogonadism is a relatively common condition in middle-aged to elderly men that can significantly impair quality of life. Besides lifestyle optimisation, androgen replacement remains the mainstay of treatment; however, its adverse effects on spermatogenesis and testicular atrophy are undesirable. Clomiphene citrate is a selective oestrogen receptor modulator that acts centrally to increase endogenous testosterone without affecting fertility. Although it has demonstrated effectiveness in shorter-duration studies, its longer-term outcomes are less well-documented. In this study, we report the case of a 42-year-old male with functional hypogonadotropic hypogonadism who sustained an excellent dose-dependent, titratable clinical and biochemical response to clomiphene citrate with no known adverse effects for 7 years to date. This case highlights that clomiphene citrate has potential as a safe and titratable longer-term treatment option, and the need for further randomised control trials in therapy options to normalise androgen status.

          Learning points
          • Functional hypogonadotropic hypogonadism is a relatively common, but likely underdiagnosed, condition in middle-aged to older males.

          • Testosterone replacement is the current mainstay of endocrine therapy but can cause sub-fertility and testicular atrophy.

          • Clomiphene citrate is a serum oestrogen receptor modulator that acts centrally to increase endogenous testosterone production without affecting fertility.

          • It has potential as a safe and efficacious longer-term treatment option that can be titrated to increase testosterone and relieve clinical symptoms in a dose-dependent manner.

          • Longitudinal prospective studies as randomised control trials evaluating alternatives to exogenous testosterone are required.

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          Most cited references25

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          Testosterone Therapy in Men With Hypogonadism: An Endocrine Society Clinical Practice Guideline

          To update the "Testosterone Therapy in Men With Androgen Deficiency Syndromes" guideline published in 2010.
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            Prevalence of hypogonadism in males aged at least 45 years: the HIM study

            The Hypogonadism in Males study estimated the prevalence of hypogonadism [total testosterone (TT) <300 ng/dl] in men aged ≥45 years visiting primary care practices in the United States. A blood sample was obtained between 8 am and noon and assayed for TT, free testosterone (FT) and bioavailable testosterone (BAT). Common symptoms of hypogonadism, comorbid conditions, demographics and reason for visit were recorded. Of 2162 patients, 836 were hypogonadal, with 80 receiving testosterone. Crude prevalence rate of hypogonadism was 38.7%. Similar trends were observed for FT and BAT. Among men not receiving testosterone, 756 (36.3%) were hypogonadal; odds ratios for having hypogonadism were significantly higher in men with hypertension (1.84), hyperlipidaemia (1.47), diabetes (2.09), obesity (2.38), prostate disease (1.29) and asthma or chronic obstructive pulmonary disease (1.40) than in men without these conditions. The prevalence of hypogonadism was 38.7% in men aged ≥45 years presenting to primary care offices.
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              Prevalence of symptomatic androgen deficiency in men.

              Despite recognition that androgen deficiency in men should be defined according to biochemical and clinical criteria, most prevalence estimates are based on low testosterone levels alone. The objective of this study was to examine the association between symptoms of androgen deficiency and low total and calculated free testosterone levels and estimate the prevalence of symptomatic androgen deficiency in men. This study was a population-based, observational survey. A total of 1,475 Black, Hispanic, and white men, between the ages of 30-79 yr, with complete data on testosterone, SHBG, and symptoms of androgen deficiency, and who are not taking medications that impact sex steroid levels were randomly selected from the Boston Area Community Health Survey. Outcomes were measured as symptomatic androgen deficiency, defined as low total (<300 ng/dl) and free (<5 ng/dl) testosterone plus presence of low libido, erectile dysfunction, osteoporosis or fracture, or two or more of following symptoms: sleep disturbance, depressed mood, lethargy, or diminished physical performance. Mean age of the sample was 47.3 +/- 12.5 yr. Approximately 24% of subjects had total testosterone less than 300 ng/dl, and 11% of subjects had free testosterone less than 5 ng/dl. Prevalence of symptoms were as follows: low libido (12%), erectile dysfunction (16%), osteoporosis/fracture (1%), and two or more of the nonspecific symptoms (20%). Low testosterone levels were associated with symptoms, but many men with low testosterone levels were asymptomatic (e.g. in men 50+ yr, 47.6%). Crude prevalence of symptomatic androgen deficiency was 5.6% (95% confidence interval: 3.6%, 8.6%), and was not significantly related to race and ethnic group. Prevalence was low in men less than 70 yr (3.1-7.0%) and increased markedly with age to 18.4% among 70 yr olds. Projection of these estimates to the year 2025 suggests that there will be as many as 6.5 million American men ages 30-79 yr with symptomatic androgen deficiency, an increase of 38% from 2000 population estimates. Prevalence of symptomatic androgen deficiency in men 30 and 79 yr of age is 5.6% and increases substantially with age. The aging of the U.S. male population will cause a large increase in the burden of symptomatic androgen deficiency. Future work should address the clinical significance of low testosterone levels in asymptomatic men.

                Author and article information

                Endocrinol Diabetes Metab Case Rep
                Endocrinol Diabetes Metab Case Rep
                Endocrinology, Diabetes & Metabolism Case Reports
                Bioscientifica Ltd (Bristol )
                11 January 2023
                : 2023
                : 22-0242
                [1 ]Department of Endocrinology , Royal Prince Alfred Hospital, Sydney, NSW, Australia
                [2 ]Sydney Medical School (Central) , University of Sydney, Sydney, NSW, Australia
                Author notes
                Correspondence should be addressed to S M Twigg; Email: stephen.twigg@ 123456sydney.edu.au
                Author information
                © The authors

                This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License..

                : 04 March 2022
                : 11 January 2023
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                adult, female, white, australia, testes, andrology, novel treatment, february, 2023


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