The risks and benefits of HRT

For many years hormone replacement therapy (HRT) was regarded as the gold standard for treatment of osteoporosis. In recent years this status has been challenged, because of the lack of a robust evidence base for anti-fracture efficacy, emerging evidence of adverse extraskeletal effects and the demonstrated efficacy of a number of alternative options in the prevention of osteoporotic fractures. The current consensus is that HRT is no longer regarded as a front-line option for prevention of osteoporotic fractures and that its use for this purpose should be restricted to women with osteoporosis who have menopausal symptoms and to older women who are intolerant of other therapies and/or express a strong preference for HRT despite being informed about potential adverse effects. Nevertheless, the mechanisms by which estrogen exerts its beneficial skeletal effects remain a major area of research that has important implications for the development of novel therapies.     

Effect of growth hormone replacement therapy on pituitary hormone secretion and hormone replacement therapies in GHD adults

OBJECTIVE: We tested the impact of commencement of GH replacement therapy in GH-deficient (GHD) adults on the circulating levels of other anterior pituitary and peripheral hormones and the need for re-evaluation of other hormone replacement therapies, especially the need for dose changes. METHODS: 22 GHD patients were investigated in a double-blind randomized study and 90 GHD patients in an open study at baseline and after 6 and 12 months of GH replacement therapy. RESULTS: In the placebo-controlled trial, the FT(3) levels increased after 6 months in the GH-treated group, and in the open study the FT(3) levels tended to increase. Other hormone concentrations did not change in either part of the study. Four patients required an increase in thyroxine dose, while 2 patients needed dose reduction. One originally euthyroid patient required thyroxine replacement. Two patients with originally conserved pituitary-adrenal function developed ACTH insufficiency. The hydrocortisone dose was increased in 1 and decreased in 1 of the 66 patients with secondary hypocortisolism. None of the females required any adjustment of sex hormone replacement therapy. Two of 37 males needed dose increase of testosterone, while 1 needed dose reduction. CONCLUSION: GH replacement therapy required dose adjustments regarding other hormone replacement therapies in 12.2% (n = 11), while initiation of new hormone replacement was performed in 3.3% (n = 3) of the 90 patients during the 1-year follow-up. Monitoring of pituitary hormone axes is advisable after commencement of GH replacement therapy, since changes of hormone replacement therapy was observed in a small but clinically significant number of patients.     

Acromegaly induced by growth hormone replacement therapy

Recombinant human growth hormone (GH) has been shown to be efficacious and safe in the treatment of various growth disorders and GH deficiency. We here report a 61-year-old man with idiopathic hypopituitarism in whom clinically active acromegaly developed. Complete GH deficiency had been diagnosed earlier by arginine stimulation testing, and therapy with recombinant human GH (maintenance dose 2 IU/day) was implemented at the age of 54 years. At presentation, the patient's insulin-like growth factor 1 (IGF-1; 439 ng/ml) and insulin-like growth factor binding protein 3 (4.3 mg/l) levels were highly elevated. Endogenous GH production and pituitary adenoma were excluded. Retrospectively, IGF-1 levels up to 621 ng/ml had been documented (but not appreciated) in the preceding 7 years. Upon GH dose reduction, the IGF-1 serum levels returned to normal, and the patient's clinical status stabilized. No GH receptor polymorphisms were identified in the patient's genomic DNA. This observation demonstrates that the indiscriminate use of recombinant GH bears the risk of active acromegaly, emphasizing the need for long-term patient monitoring programs as integral part of GH therapy.     

Benefits and risks of circumcision.

Circumcisions are performed either prophylactically in the neonatal period or therapeutically at a later age. About 10% of males not circumcised at birth will eventually require circumcision. The present neonatal circumcision rate is about 80% in the United States and 40% in Canada. The single most important determinant of whether a newborn male will be circumcised is the attitude of the attending physician. The literature was reviewed to determine the proven benefits of circumcision and to compare these with the known risks. Circumcising the newborn facilitates penile hygiene, prevents cancer of the penis and decreases the incidence of genital herpes in later life. Whether it decreases the incidence of cancer of the cervix is still uncertain. More important, neonatal circumcision is associated with much lower morbidity and mortality and with lower costs than therapeutic circumcision. Thus, prophylactic circumcision is recommended for the male population as a whole.     

Pharmacogenetics of hormone replacement therapy for climacteric symptoms

Hormone replacement therapy (HRT) is highly effective for women suffering from climacteric symptoms, with occasionally severe side effects. To determine which women needs HRT for climacteric symptoms indeed, pharmacogenetical approach for HRT was performed. Under the condition of minimal HRT, 33 patients required HRT for more than 1 year and the remaining 156 did not. Three single nucleotide polymorphisms (SNPs) in estrogen receptor α (ERα) gene and 3 SNPs and a microsatellite polymorphism in estrogen receptor β (ERβ) gene were analyzed using LightTyper and PCR. Homozygous for 18 CA repeats of D14S1026 (OR 8.00, 95% CI 2.56-25.02, P < 0.001) and rs1256049 (OR 6.35, 95% CI 2.38-16.92, P = 0.004) in ERβ associated with minimal HRT. In contrast, rs1271572 in 789 bp upstream region of ERβ (OR 0.30, 95% CI 0.14-0.65, P = 0.002) gene decreased HRT. rs2228480 in ERα gene also increased HRT. Tailored decisions can be expected on the future use of HRT referring genetic polymorphisms of individuals.     

The menopause,hormone replacement therapy and breast cancer

Concern exists that the reduction in breast cancer risk associated with the onset of the menopause will be negated with exposure to hormone replacement therapy (HRT). Evidence from large-scale randomised HRT trials support observational data that have shown a modest increase in breast cancer risk with long-term use (i.e. >15 years) of combined therapy, although this falls following HRT cessation suggesting a growth-promoting effect. Randomised evidence demonstrates that the efficacy of anti-estrogens, aromatase inhibitors and raloxifene in the treatment and chemoprevention of breast cancer are restricted to women with oestrogen receptor positive (ER +ve) disease; however, HRT has not been associated conclusively with a predominance of hormone sensitive breast cancer. Despite stimulating the breast cancer cell growth, HRT has not been shown to increase breast cancer recurrence or mortality when prescribed to breast cancer survivors experiencing oestrogen deficiency symptoms and randomised trials have been recommended and commenced. In conjunction with controlled breast cancer trials demonstrating a therapeutic benefit of high dose estrogens and interest in the use of additive oestrogen therapy in patients developing resistance to oestrogen deprivation, the dogma that HRT is an absolute contra-indication following diagnosis is challenged.     

Incidences of breast cancer throughout long-term hormone replacement therapy

OBJECTIVE: To report the main incidences related to diagnosis of breast cancer in a randomly selected cohort population of women treated with conjugated equine estrogens (CEE), always in conjunction with the opposed progestin, medroxy progesterone acetate (MPA) throughout prolonged oral administration. MATERIAL AND METHODS: One hundred and seventy-eight women were subsequently studied before and during the treatment (cohort study). The profile of studied patients included family and personal histories, gynecological and breast examinations, basal hormonal levels, bone mass concentration (BMC) as well as total cholesterol levels and their fractions. The usual clinical cut off age was applied at the beginning of treatment according to following criteria: (a) women less than 60 years old (91.60%), and (b) women more than 60 years old (8.40%), by assuming that a primary protective effect of HRT might be lost or diminished after surpassing this age threshold. In all the treated women were thoroughly advised about the importance of diet, exercises and self-determination. Both oral CEE 0.625 mg/daily and either 2.5 mg/daily or 5 mg/daily of MPA were administrated in accordance with The American Fertility Society Meeting after 1995 (Seattle) recommendations, following two patterns: (1) cycles or perimenopausal women: from days 1 to 25, and (2) postmenopausal women, from Monday to Friday. No other specific treatments were prescribed. Statistical analysis was performed by using SPSS 12.0 and G-stat 2.0. RESULTS: Evaluation of basal hormonal levels, BMC, cholesterol levels and their fractions were not included in the current study. Data from the statistical analysis of 178 treated women were as follow: mean duration of treatment 8.06 years for all women; in the younger age group 7.97, and in the older age group 9.04. Total of 1405.5 woman-years of follow-up, 119 women for more than 5 years (66.85%), and more times (68.18%) with CEE plus MPA 5 mg/daily regime. Dropouts occurred in 34 women (19.10%). Main incidences: no deaths occurred during the treatment. Four cardiovascular events (2.24%) were reported. No spontaneous bone fractures were documented. Nonetheless, there were 11 bone fractures of traumatic origin (6.17%), none of them hip fractures. Four breast cancer. Likewise, one diagnosis of breast cancer in each of 45 treated women from our series was evidenced. One hundred and twenty-one women (67.97%) without incidences. COMMENTS: In our cohort study advices on diet, exercises and self-determination were reinforced for 1405.5 woman-years of follow-up. Combined CEE plus MPA for more than 5 years are no more risk related to breast cancer and cardiovascular events versus shorter treatments. Long-term CEE plus MPA were well tolerated and we did not find statistical evidence which would allow deducing higher rates of morbidity in those entities. Likewise, no deaths were document during the treatments.     

Utilisation of hormone replacement therapy by women doctors.

OBJECTIVES--To ascertain the prevalence and duration of use of hormone replacement therapy by menopausal women doctors. DESIGN--Postal questionnaire. SETTING--General practices in the United Kingdom. SUBJECTS--Randomised stratified sample of women doctors who obtained full registration between 1952 and 1976, taken from the current principal list of the Medical Register. MAIN OUTCOME MEASURES--Prevalence and duration of use of hormone replacement therapy; menopausal status. RESULTS--Overall, 45.7% (436/954) of women doctors aged between 45 and 65 years had ever used hormone replacement therapy. When the results from women still menstruating regularly were excluded, 55.2% (428) were ever users and 41.2% (319) current users. The cumulative probability of remaining on hormone replacement therapy was 0.707 at five years and 0.576 at 10 years. CONCLUSIONS--Women doctors have a higher prevalence of use of hormone replacement therapy than has been reported for other women in the United Kingdom, and most users seem to be taking hormone replacement therapy for more than five years. The results may become generalisable to the wider population as information on the potential benefits of hormone replacement therapy is disseminated.