Sex Steroid Replacement Therapy Research Articles

Replicative and biochemical ageing features among females with primary ovarian insufficiency

One of the most dangerous reproductive pathologies is primary ovarian insufficiency (POI). Except manifestation in the age <40 years old it leads to demographical losses, decrease of chances for healthy aging. POI can be characterized as summary of secondary amenorrhea, total estrogenic deficiency and hypergonadotropic hypogonadism. Hence, POI has probably harmful effect on telomere length. Telomere length determining and sex steroid replacement therapy may be promising and effective to prevent decrease of life quality/ longevity among females with POI. To evaluate features of replicative (telomere length) and biochemical (metabolic syndrome) markers among females with primary ovarian insufficiency. Research has been provided in collaboration between Endocrinology Research Centre of the Russian Ministry of Health and Lomonosov Moscow State University Medical Research and Educational Centre in the period since 10.01.2021 until 01.08.2022. Females with non-iatrogenic hypergonadotropic hypogonadism caused by primary ovarian insufficiency (n=33); healthy females of reproductive age (18-49 y.o.; n=24). Patients have undergone laboratory genetic (leucocyte telomere length), biochemical analyses. DNA extraction - with Qiagen DNA blood mini kit (Germany).Leukocyte telomere length - with real-time polymerase chain reaction PCR (Flow-fish). Soft program IBM SPSS Statistics (version 26,0 for Windows). Females with POI due to estrogenic deficiency have slightly shorter mean telomere length (10,0 [7,9-10,7] kB, than healthy females of reproductive age (10,8 [10,0-13,1] кБ, р<0,001). Females with POI due to estrogenic deficiency have higher chances for development of carbohydrate metabolism disturbances (prediabetes) (р<0,043), increasement of FSH level (р<0,001). FSH level correlates moderately and negatively (ρ=0,434) with leukocyte telomere length (р<0,001). Female with POI and receiving sex steroid replacement therapy have decrease of telomere length and increase of chances for carbohydrate metabolism disturbances in opposite to healthy reproductive females.

Bone mineral density during 3 years of growth hormone in previously GH-treated young adults with PWS.

In children with Prader-Willi syndrome (PWS), growth hormone (GH) treatment has positive effects on bone mineral density (BMD). Two 1-year studies did not show a difference between GH or placebo on BMD in young adults with PWS. However, there are no studies investigating BMD during longer-term GH treatment in young adults with PWS. Open-label, a prospective study in 43 young adults with PWS. BMD of the total body (BMDTBSDS) and lumbar spine (BMADLSSDS) measured by DXA. In the total group, estimated mean (95% CI) of BMDTB remained similar during 3 years of GH, being -0.76 (-1.11 to -0.41) SDS at start and -0.90 (-1.27 to -0.54) SDS after 3 years (P = 0.11), as did BMADLS, being -0.36 (-0.72 to 0.01) SDS and -0.46 (-0.77 to -0.16) SDS, respectively (P = 0.16). In men, there was a significant decrease in BMDTBSDS during 3 years of GH, while BMADLSSDS remained similar. In women, both BMDTBSDS and BMADLSSDS remained similar. BMDTBSDS was associated with female sex, lean body mass and age. The majority of patients received sex steroid replacement therapy (SSRT). During 3 years of combined GH and SSRT treatment, BMD remained stable in the normal range in young adults with PWS. However, men showed a decline in BMDTBSDS, probably due to insufficient SSRT. We recommended to continue GH treatment in young adults with PWS and to start SSRT during adolescence unless puberty progresses normally.

Bone mineral density in young adults with Prader‐Willi syndrome: A randomized, placebo‐controlled, crossover GH trial

The prevalence of osteoporosis is increased in adults with Prader-Willi syndrome (PWS). In children with PWS, growth hormone (GH) treatment has beneficial effects on bone mineral density (BMD). BMD might deteriorate after cessation of GH at adult height (AH), while continuing GH might maintain BMD. To investigate the effects of GH vs placebo, and furthermore the effects of sex steroid replacement therapy (SSRT), on BMD in GH-treated young adults with PWS who had attained AH. Two-year, randomized, double-blind, placebo-controlled, crossover GH study. Twenty-seven young adults with PWS were stratified for gender and BMI and then randomly and blindly assigned to receive GH (0.67mg/m2 /day) or placebo for 1 year, after which they crossed over to the alternative treatment for another year. Bone mineral density of the total body (BMDTB ) and lumbar spine (BMDLS ) SDS were measured by dual-energy x-ray absorptiometry. At AH, BMDTB SDS was significantly lower compared to healthy peers (P<.01), while BMADLS SDS was similar. Both BMDTB SDS and BMADLS SDS were similar during 1year of GH vs 1year of placebo. In hypogonadal young adults without SSRT, BMDTB SDS and BMADLS SDS decreased during the 2-year study (P=.11 and P=.01), regardless of GH or placebo, while BMDTB SDS increased in those with SSRT (P<.01). Compared to GH treatment, 1year of placebo after attainment of AH does not deteriorate BMD SDS in young adults with PWS. In addition, our data suggest that GH is not able to prevent the decline in BMD SDS in hypogonadal young adults with PWS, unless it is combined with SSRT.

Premature ovarian insufficiency - hormone replacement therapy and management of long-term consequences.

Premature ovarian insufficiency (POI) correlates with increased risk of cardiovascular diseases, osteoporosis, genitourinary syndrome, and other symptoms of prolonged oestrogen deprivation. Properly selected therapy improves the quality of women’s lives and reduces the risk of mortality. There is a wide spectrum of available oestrogen and progestogen formulations restoring proper levels of serum sex steroid hormones. The treatment should be implemented at recognition of the POI and continued to at least the age of natural menopause. Transdermal oestradiol and oral or vaginal progesterone administration provide the most physiological sex steroid replacement therapy. Patients’ views and individual preference according the route, dose, and regimen of hormonal treatment have to be taken into consideration in order to achieve high compliance rates. Women with POI should be managed by a multidisciplinary team, such as a gynaecologist, endocrinologist, dietitian, and psychologist.

Update on the Genetics of Idiopathic Hypogonadotropic Hypogonadism.

Traditionally, idiopathic hypogonadotropic hypogonadism (IHH) is divided into two major categories: Kallmann syndrome (KS) and normosmic IHH (nIHH). To date, inactivating variants in more than 50 genes have been reported to cause IHH. These mutations are estimated to account for up to 50% of all apparently hereditary cases. Identification of further causative gene mutations is expected to be more feasible with the increasing use of whole exome/genome sequencing. Presence of more than one IHH-associated mutant gene in a given patient/pedigree (oligogenic inheritance) is seen in 10-20% of all IHH cases. It is now well established that about 10-20% of IHH cases recover from IHH either spontaneously or after receiving some sex steroid replacement therapy. Moreover, there may be an overlap or transition between constitutional delay in growth and puberty (CDGP) and IHH. It has been increasingly observed that oligogenic inheritance and clinical recovery complicates the phenotype/genotype relationship in IHH, thus making it challenging to find new IHH-associated genes. In a clinical sense, recognizing those IHH genes and associated phenotypes may improve our diagnostic capabilities by enabling us to prioritize the screening of particular gene(s) such as synkinesia (ANOS1), dental agenesis (FGF8/FGFR1) and hearing loss (CHD7). Also, IHH-associated gene studies may be translated into new therapies such as for polycystic ovary syndrome. In a scientific sense, the most significant contribution of IHH-associated gene studies has been the characterization of the long-sought gonadotropin releasing hormone pulse generator. It appears that genetic studies of IHH will continue to advance our knowledge in both the biological and clinical domains.

Hypogonadism and Sex Steroid Replacement Therapy in Girls with Turner Syndrome

Turner syndrome is the most common example of hypergonadotropic hypogonadism resulting from gonadal dysgenesis. Most patients present delayed, or even absent, puberty. Premature ovarian failure can be expected even if spontaneous menarche occurs. Laboratory markers of gonadal dysgenesis are well known. The choice of optimal hormone replacement therapy in children and adolescents remains controversial, particularly regarding the age at which therapy should be initiated, and the dose and route of estrogen administration. On the basis of a review of the literature, we present the most acceptable schedule of sex steroid replacement therapy in younger patients with Turner syndrome.

Sex Steroid Replacement Therapy in Female Hypogonadism from Childhood to Young Adulthood.

The overall goal of pubertal sex hormone replacement therapy (HRT) in girls is not only about development of secondary sexual characteristics, but also to establish an adult endocrine and metabolic milieu, as well as adult cognitive function. Estradiol (E2) is the first choice for HRT compared to ethinyl estradiol (EE2). E2 is the most potent endogenous estrogen in the circulation, with established levels during spontaneous puberty. Transdermal E2, compared to oral administration, is the first choice to start pubertal HRT. Transdermal application avoids liver exposure to supraphysiologic estrogen concentrations and provides a more physiologic mechanism for hormone delivery. By cutting E2 matrix patches in doses of 0.05-0.07 µg/kg or administrate E2 gel in doses of 0.1 mg/day, serum concentrations of E2 seen in early spontaneous puberty can be obtained. Patches can be removed in the morning and thereby mimic the normal circadian rhythm. For those clinics with access to sensitive E2 determinations methods (extraction followed by radioimmunoassay or mass spectrometry) monitoring the attained E2 serum levels is recommended in order to optimally mimic the levels seen in early puberty as well as growth velocity, breast and uterus development. Mid- and late pubertal HRT is obtained by increased doses of E2, adding cyclic oral or transdermal progestin, as well as testosterone gel over the pubic area if indicated.

Endocrine Investigation and Follow Up in Thalassaemia. Time for Specific Guidelines

Iron overload due to multiple transfusions affects the endocrine glands especially the anterior pituitary, the pancreas, the thyroid and the parathyroids. This leads to a variety of endocrinopathies and growth failure. Delayed puberty, hypogonadism, growth hormone deficiency in adults, hypothyroidism, hypoparathyroidism and diabetes are common and around 20% of patients have more than one endocrinopathy. In this paper suggestions for guidelines concerning diagnosis, investigation and treatment are proposed for the following clinical entities encountered in thalassaemia patients: (i) Growth failure: after the age of 9–10 rears there is a slowing of growth velocity, the pathogenesis of which is multifactorial and anaemia, folate deficiency and hypersplenism are implicated. Desferrioxamine toxicity has been reported as cause of the abnormal upper to lower segment ratio. Growth hormone is given in selected cases. (ii) Delayed puberty and hypogonadism: are the most obvious clinical consequences of iron overload in both sexes. Primary and secondary amenorrhoea are very common in women. Sex steroid replacement therapy is the optimal therapeutic regime which has a great impact on the quality of life of adult thalassaemia patients. (iii) Fertility: Women with TM, who are regularly transfused and are well chelated can now become pregnant either spontaneously or by inducing ovulation. Pregnancy must carefully monitored. (iv) Growth hormone deficiency in adult thalassaemics: This occurs in a high prevalence and since GH in adults is involved in numerous biological functions, especially of the heart, proper assessment of this hormone is needed and consideration of the need for replacement. (v) Hypothyroidism and hypoparathyroidism: these deficiencies are also discussed.

Cardiovascular Effects of Physiological and Standard Sex Steroid Replacement Regimens in Premature Ovarian Failure

Current hormone replacement therapy may not optimize cardiovascular health in women with premature ovarian failure. We compared the effects of physiological and standard sex steroid replacement regimens on cardiovascular health in these women. In an open-label, randomized, controlled crossover trial, 34 women with premature ovarian failure were randomly assigned to 4-week cycles of physiological (transdermal estradiol and vaginal progesterone) and standard (oral ethinylestradiol and norethisterone) therapy for 12 months. Cardiovascular health was assessed by 24-hour ambulatory blood pressure, arterial stiffness, and renal and humoral factors. Eighteen women (19 to 39 years of age) completed the 28-month protocol. Both regimens caused similar suppression of luteinizing hormone and follicle-stimulating hormone and provided symptom relief. In comparison with the standard regimen, physiological sex steroid replacement caused lower mean 24-hour systolic and diastolic blood pressures throughout the 12-month treatment period (ANOVA; P<or=0.0001 for both): systolic blood pressure was 7.3 mm Hg (95% CI: 2.5 to 12.0 mm Hg) and diastolic was 7.4 mm Hg (95% CI: 3.9 to 11.0 mm Hg) lower at 12 months. Although there were no differences in arterial stiffness, physiological sex steroid replacement reduced plasma angiotensin II (ANOVA; P=0.007) and serum creatinine (ANOVA; P=0.015) concentrations without altering plasma aldosterone concentrations. In comparison with a standard regimen, physiological sex steroid replacement in women with premature ovarian failure results in lower blood pressure, better renal function, and less activation of the renin-angiotensin system. These findings have major implications for the future cardiovascular health of young women who require long-term sex steroid replacement therapy.

Recombinant human growth hormone in the treatment of Turner syndrome

Turner syndrome (TS) is a common chromosomal disorder in women that is associated with the absence of one of the X chromosomes. Severe short stature and a lack of pubertal development characterize TS girls, causing psychosocial problems and reduced bone mass. The growth impairment in TS seems to be due to multiple factors including an abnormal growth hormone (GH) - insulin-like growth factor (IGF) - IGF binding protein axis and haploinsufficiency of the short stature homeobox-containing gene. Growth hormone and sex steroid replacement therapy has enhanced growth, pubertal development, bone mass, and the quality of life of TS girls. Recombinant human GH (hGH) has improved the height potential of TS girls with varied results though, depending upon the dose of hGH and the age of induction of puberty. The best final adult height and peak bone mass achievement results seem to be achieved when hGH therapy is started early and puberty is induced at the normal age of puberty in a regimen mimicking physiologic puberty. The initiation of estradiol therapy at an age-appropriate time may also help the TS patients avoid osteoporosis during adulthood. Recombinant hGH therapy in TS seems to be safe. Studies so far show no adverse effects on cardiac function, glucose metabolism or any association with neoplasms but research is still in progress to provide conclusive data on long-term safety.

The effects of sex steroid replacement therapy on an expanded panel of IGF-related peptides

Background Oral estrogen alone (EA) decreases concentrations of total IGF-I while increasing IGFBP-1, but data on other IGF-related peptides are inconsistent and/or sparse. Combined oral estrogen and progestin (EP) may have differential effects on IGF-related peptides dependent on its progestin-associated androgenic activity. The aim of this study was to clarify these relationships, as circulating IGF-related peptides are potential surrogates of predisposition to common chronic diseases. Design Using an open-labelled cross-sectional design within a bowel cancer screening trial (aged 55–64 years), we determined total IGF-I, IGF-II, IGFBP-2 and IGFBP-3 in fasted serum from 210 healthy women and free IGF-I (by ultrafiltration), insulin, IGFBP-1 and IGFBP-1:IGF-I binary complex in a selected subset of 92 women. Unadjusted and adjusted (using generalized linear models) means were compared. Results Among EA users, mean concentrations for total IGF-I (adjusted P = 0.004) and free IGF-I ( P < 0.001) were reduced, whereas mean concentrations of IGFBP-1 ( P = 0.001) and binary complex ( P = 0.01) were increased compared with non-users. Taken as a whole group, EP use was not associated with differences in concentrations of IGF-related peptides, but on sub-group analyses, mean concentrations associated with the use of progestins with reduced androgenic activity reflected the use of EA. By contrast, mean IGFBP-2 concentrations were significantly reduced among both EA ( P = 0.008) and EP ( P = 0.002) users, irrespective of androgenic activity. Neither EA nor EP influenced mean concentrations of IGF-II, insulin and IGFBP-3. Conclusions The uses of oral sex steroid replacements are associated with significant changes in several IGF-related analytes in a preparation-specific manner, suggesting different regulatory mechanisms. However, the directions of these changes do not fit simple correlative models of predisposition to common diseases.

Diagnosis and management of pituitary tumours in the elderly: a review based on personal experience and evidence of literature

An increasing proportion of pituitary adenomas are recognized in the elderly, raising the question of their optimal diagnosis and management. Age-related endocrine changes and associated diseases may significantly modify the clinical presentation and hormonal evaluation of these patients. About 80% of pituitary adenomas in this age group are non-secreting, requiring careful differential diagnosis with non-adenomatous sellar lesions. In this group, visual deterioration and hypopituitarism remain the leading symptoms. Recognized secreting tumours are mainly GH-secreting, most of them intrasellar, followed by prolactinomas, which present as clinically non-secreting and are usually invasive. Cushing's disease appears as a very rare eventuality in the elderly. Optimal therapeutic management should aim to control the disease while preserving or improving patient's quality of life. Transsphenoidal surgery has proved to be an efficient and well-tolerated option for non-secreting adenomas with visual defects and intrasellar GH-secreting adenomas, being able to improve metabolic and cardiovascular complications of acromegaly even in this age group. In contrast, dopamine-agonist drugs can be proposed as a primary therapy for prolactinomas even in the presence of severe neurological complications. Because the use of radiotherapy is hampered by its delay of action and potential neurological side effects, its indications should be better defined in this age group. The clinical importance of hypopituitarism should not be underestimated, and thyroid- and adrenal-replacement therapy are mandatory in the presence of documented hormone deficiency, carefully avoiding overtreatment in order to limit possible side effects on the cardiovascular system and bone mineralization. Indications for GH- and sex steroid-replacement therapy still await age-specific guidelines.

Pituitary hormone replacement

<h2>Abstract</h2> Hormone replacement therapy is available for patients suffering diabetes insipidus and all the anterior pituitary hormone deficiencies, with the exception of prolactin. In patients with adrenocorticotrophic hormone and thyroid-stimulating hormone deficiencies, replacement is with the target-gland hormone products cortisol (hydrocortisone) and thyroxine, respectively. Sex steroid replacement therapy is offered to patients with gonadotrophin deficiency to deal with the sex steroid deficiency, but if fertility is desired gonadotrophin therapy is required. Growth hormone (GH) deficiency requires GH replacement, but only adult patients with severe GH deficiency are considered for replacement and, in the UK, such patients are chosen by virtue of severe impairment of quality of life; strict criteria must be satisfied before the 9-month trial of therapy can be extended to lifelong GH replacement. Desmopressin, a synthetic analogue of arginine vasopressin, is the drug of choice for the treatment of antidiuretic hormone deficiency; it is available in several different preparations.

Prevention of Bone Loss after Allogeneic Stem Cell Transplantation by Calcium, Vitamin D, and Sex Hormone Replacement with or without Pamidronate

In controlled studies, bisphosphonates have been used to prevent bone loss after solid organ transplantations but not in conjunction with stem cell transplantation (SCT). The objective of the study was to test whether additional iv pamidronate would prevent bone loss associated with SCT more effectively than the combination of calcium, vitamin D, and sex steroid replacement therapy alone. The study was carried out at the Helsinki University Central Hospital. PATIENTS, DESIGN, INTERVENTION: Ninety-nine adult recipients of allogeneic SCT were randomized by age and gender into two groups. In one group, the patients received 1000 mg calcium carbonate and 800 IU vitamin D daily, and females received estrogen and males received testosterone replacement therapy. In another group, the patients received the same treatments plus six iv infusions of 60 mg pamidronate before and 1, 2, 3, 6, and 9 months after SCT. Bone mineral density (BMD) of the lumbar spine and the upper femur, measured by dual-energy x-ray absorptiometry, and bone turnover markers were followed for 12 months. In the pamidronate group, lumbar spine BMD remained stable but decreased in the other group by 2.9% at 12 months (P = 0.0084 between the groups over time). Total hip BMD reduced 5.1% in the pamidronate group and 7.8% in the other group by 12 months (P = 0.0015), and femoral neck BMD reduced 4.2 and 6.2%, respectively (P = 0.074). In the pamidronate group, serum type I procollagen amino-terminal propeptide (P = 0.032 between the groups over time) and urinary type I collagen amino-terminal telopeptide (P = 0.035) decreased 79 and 68% during the first 3 months, and remained lowered thereafter, but did not change in the other group. The recipients of allogeneic SCT receiving additional pamidronate sustain less bone loss than those treated with calcium, vitamin D, and sex steroid replacement alone. Despite all the efforts, however, bone loss is not totally abolished at the hip.

Lp(a) and lipids in adult Turner’s syndrome: impact of treatment with 17β-estradiol and norethisterone

Turner’s syndrome is associated with a high incidence of cardiovascular disease and hypothyreosis; conditions which are associated with abnormal lipid metabolism. To test whether alterations of lipid metabolism is present in healthy Turner’s women, we compared lipids in a group of adult women with Turner’s syndrome with an age matched group of healthy women. In addition the impact of sex steroid replacement therapy was studied in the women with Turner’s syndrome. Patients were studied before and during treatment with hormonal replacement therapy, consisting of either oral 17β-estradiol or transdermal 17β-estradiol, and oral norethisterone. Control subjects were studied once in the early follicular stage of the menstrual cycle. The study group consisted of 26 (33.2±7.9 years) patients with Turner’s syndrome and an age matched control group of 24 (32.7±7.6 years) normal women. Body composition measures, apolipoprotein (apo) B and apo A-I, Lp(a), cholesterol, HDL, LDL, triglycerides, thyroxine (TT4), free thyroxine (FT4), triiodothyronine (TT3), free triiodothyronine (FT3), TSH, and leptin were determined. Apo A-I levels were higher in Turner’s patients ( P=0.007), while levels of Lp(a) were comparable in the two groups. Only when the participants were divided into groups of low (≤45 g/l) and high (>45 g/l) Lp(a), more women with Turner’s syndrome had high levels of Lp(a) than controls ( P=0.024), while all other measures of lipid metabolism were comparable to controls. The level of TSH, FT3, and FT4 were significantly higher in Turner’s patients, while TT4, TT3 and adjusted 24h energy expenditure were comparable to controls. Lp(a) ( P=0.005), HDL ( P=0.045) and apo A-I ( P=0.039) decreased significantly, while there was a tendency towards a decrease in apo B ( P=0.063) during treatment with sex hormones. In conclusion more women with Turner’s syndrome than controls have high levels of apolipoprotein A-I and Lp(a), but only after dichomitization, while other markers of lipid metabolism are normal. Replacement therapy with female sex hormones lowered Lp(a), HDL cholesterol and apolipoprotein A-I.

Sexual dimorphism of cortisol metabolism is maintained in elderly subjects and is not oestrogen dependent.

The net interconversion of inactive cortisone to active cortisol by 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) may determine hepatic and adipose tissue exposure to glucocorticoid action. Cortisol metabolism exhibits a sexual dimorphism with an apparently lower activity of 11betaHSD1 in females that, in an animal model, has been attributed to the effects of oestrogen. The aim of this study is to determine whether the sexual dimorphism of cortisol metabolism persists between post-menopausal, oestrogen-deficient women and elderly men. Fifteen healthy men, aged 60.8-82.0 years, and 7 healthy women, aged 62.4-87.5 years, were studied. None of the subjects was receiving steroid medication at the time of the study. All the women were post-menopausal and none was receiving sex steroid replacement therapy. 24-h urine collections were taken from each patient and assayed for steroid metabolites by gas chromatography. Body composition was determined by dual energy X-ray absorptiometry. Blood was drawn, after an overnight fast, for the determination of serum IGF-I and IGFBP1 levels. The ratio of 11-hydroxy cortisol metabolites to 11-oxo cortisol metabolites (Fm/Em) was significantly higher in men than in women, 0.80 (0.55-1.86) vs. 0.67 (0.46-0.98) (P < 0.02), as was the ratio of allo-tetrahydrocortisol (5alpha-THF) + tetrahydrocortisol (THF)/tetrahydrocortisone (THE), 0.74 (0.37-2.08) vs. 0.40 (0.22-1.10) (P < 0.047). In the group as a whole there was a negative correlation between Fm/Em and percent body fat, r = - 0. 43 (P < 0.05), and the negative relationship between cortisol and cortisone metabolite (Fm/Em) and total fat mass approached significance, r = - 0.39 (P = 0.07). These relationships were not apparent in the women when considered alone. Among the men there were negative relationships between Fm/Em and total fat mass, r = - 0.48, and Fm/Em and trunk fat mass, r = - 0.48 which approached significance (both P = 0.07). Serum IGFBP-1 levels were not significantly different between the two sexes. There was a significant correlation between IGFBP-1 and Fm/Em in the men, r = 0. 84 (P < 0.0001) which persisted when total body fat mass, r = 0.85 (P < 0.0001) and trunk fat mass, r = 0.83 (P < 0.0001), were controlled for. This relationship was not evident among the women. This study demonstrates that the previously described sexual dimorphism in cortisol metabolism is not dependent on oestrogen, although the possibility that oestrogen exerts a permanent modifying effect on 11beta-HSD1 gene expression during the pre-menopausal period cannot be excluded. The findings confirm the primary importance of body fat as a determinant of cortisol-cortisone conversion.

Ultrasound B-mode changes in the uterus and ovaries and Doppler changes in the uterus after total body irradiation and allogeneic bone marrow transplantation in childhood.

Internal genitalia and uterine blood flow were assessed by ultrasound in 12 females 4.0-10.9 years after total body irradiation and allogeneic bone marrow transplantation for childhood leukaemia or lymphoma. Median age of the participants was 12.7 years (range 6.1-17.6) at bone marrow transplantation and 21.5 years (11.6-25.6) at the follow-up study. At follow-up all had entered puberty and 11/12 females had experienced the menarche. Eight females received sex steroid replacement therapy, three had spontaneous pubertal development and one woman experienced symptoms of estrogen deficiency. Median uterine and ovarian volumes were significantly reduced to -2.6 standard deviation scores (SDS) (-6.3 to -0.6), P = 0.002, and -2.6 SDS (-4.8 to -0.5), P = 0.002, respectively, compared with normal controls. Follicles were only detectable in two individuals. Uterine blood flow was impaired, as a systolic blood flow could be measured in 6/9 individuals, and a diastolic blood flow in 1/9 females. Our results indicate that the prescribed dosage of hormone replacement therapy, which was sufficient to induce bleeding and suppress other stigmata of premature menopause, was inadequate to generate normal uterine growth. In order to achieve uterine growth higher doses of hormone replacement therapy may be required. Our results confirm pelvic ultrasound as a reliable tool for investigation of internal female genitalia; however, in an infertility setting further tests are indicated.

Increased disorderliness and decreased mass and daily rate of endogenous growth hormone secretion in adult turner syndrome: the impact of body composition, maximal oxygen uptake and treatment with sex hormones

The objectives of this study were to (1) quantify pulsatility and orderliness of 24-h growth hormone (GH) secretion in adult Turner syndrome; (2) study the impact of sex steroid replacement therapy in adult Turner syndrome on these measures of GH secretion, and in addition examine the differential effect of oral vs transdermal estrogen administration on GH secretion patterns. To these ends, we used deconvolution analysis and approximate entropy (ApEn) to quantify GH release over 24 h in 21 patients with Turner syndrome before and during sex hormone substitution, compared to an age-matched control group. Deconvolution analysis revealed that the mass of GH secreted per burst and production rate was significantly lower in Turner patients compared to controls, resulting in a significantly lower integrated 24-h GH concentration. However, multiple stepwise regression revealed that lean body mass (LBM) and maximal oxygen uptake were significant discriminative variable, explaining a large part of the variation in mass secreted per burst (r = 0.72, P < 0.0005) and production rate (r = 0.73, P < 0.0005), while group (Turner or control) did not explain any of the difference. There was a significant difference in ApEn between Turner patients and controls, denoting more disorderly GH release in Turner syndrome. During administration of sex hormones, a significant increase was seen in basal secretion and GH secretory burst half-duration, as well as in integrated 24-h GH concentration. No change in ApEn was evident. We conclude that GH secretion in adult Turner syndrome is irregular, reduced in mass and production rate. The reduction in mass and production rate could be explained by differences in body composition and maximal oxygen uptake compared to relevant controls, while the irregularity of GH secretion was unexplained by the measured variables. We hypothesize that the increased irregularity could be attributable to low levels of circulating androgens or an increased biological age in the Turner patients.

Ovulation induction in a woman with premature ovarian failure resulting from a partial deletion of the X chromosome long arm, 46,X,del(X)(q22)

Objective: To report successful ovulation induction in a woman with premature ovarian failure (POF) resulting from a partial Xq deletion. Design: An uncontrolled study. Setting: University hospital. Patient(s): A 27-year-old woman with 46,X,del(X)(q22) who had hypergonadotropic secondary amenorrhea. Intervention(s): Injections of hMG (225 IU/d) for 8 consecutive days after endogenous gonadotropin suppression with a long-acting GnRH agonist (900 μg/d) for 12 weeks, together with cyclic sex steroid replacement therapy. Main Outcome Measures: Serum concentrations of E 2 and P as well as ultrasonography. Result(s): Folliculogenesis and ovulation. Conclusion(s): Ovulation induction is possible in patients with POF caused by X chromosome aberrations.

High-dose estrogen-progestogen injections in gonadal dysgenesis, ovarian hypoplasia, and androgen insensitivity syndrome: Impact on bone density

Osteopenia is common in gonadal dysgenesis when no sex steroid replacement therapy is carried out. Four patients with gonadal dysgenesis, one with ovarian hypoplasia, and one with androgen insensitivity syndrome, all having osteopenia, were treated by high-dose estrogen-progestogen injections (so-called “pseudopregnancy”) for 6 months. Each patient showed considerable increase in lumbar spine bone mineral density and impressive secondary sexual development during therapy.