Low saliva progesterone concentrations are associated with spontaneous early preterm labour (before 34 weeks of gestation) in women at increased risk of preterm delivery.

Saliva progesterone and oestriol concentrations were determined weekly from 24 weeks of gestation in women at increased risk of preterm delivery. Samples were analysed from 28 women with spontaneous onset of labour and delivery before 37 weeks of gestation, and 64 who delivered at term. Saliva progesterone was lower in the 12 women delivering before 34 weeks than in those delivering later, between 34 and 37 weeks (P = 0.007) or at term (P = 0.009). Measurement of saliva progesterone may be of value in the prediction of early preterm labour and in determining which women might benefit from progesterone supplementation.

Chemoreflex contribution to adrenocortical function during acute hypoxemia in the llama fetus at 0.6 to 0.7 of gestation.

This study tested the hypothesis that the fetal llama, a species adapted to the chronic hypoxia of life at high altitude, demonstrates a potent carotid chemoreflex influence on adrenocortical responses during acute hypoxemia. Plasma ACTH and cortisol concentrations, and mesencephalic and adrenal blood flows were measured during a 1-h period of acute hypoxemia in six intact and four carotid sinus-denervated llama fetuses at 0.6-0.7 of gestation. Fetal PaO2 was reduced from approximately 23 to about 14 mm Hg in both intact and carotid-denervated groups during acute hypoxemia. During hypoxemia, fetal plasma ACTH, adrenal blood flow, and, therefore, delivery of ACTH to the adrenals increased to similar extents in both intact and carotid-denervated fetal llamas. Despite this, the increase in plasma cortisol in hypoxemia in intact fetuses was absent in carotid-denervated fetuses. In addition, the increase in delivery of cortisol to the mesencephalon calculated in intact fetuses during hypoxemia did not occur in the carotid-denervated group. These data suggest that the integrity of the carotid chemoreceptors is indispensable to cortisol release during acute hypoxemia in the llama fetus, even at 0.6-0.7 of gestation.

The increase in plasma and saliva cortisol levels in pregnancy is not due to the increase in corticosteroid-binding globulin levels.

Total and free cortisol levels are significantly elevated in pregnancy, but the reasons for this are not clear. The relationships between the diurnal variation in saliva (free) cortisol and baseline levels of total cortisol, corticosterone-binding globulin (CBG), progesterone, and estrogens were studied in several groups of women (normal nonpregnant, taking a combined oral contraceptive pill, after superovulation therapy, during early and late pregnancy, and postpartum). Saliva cortisol levels were significantly elevated in late pregnancy throughout the day, with preservation of diurnal variation. Total cortisol and CBG levels were also significantly raised in pregnancy, but total cortisol levels were normal in women taking a combined oral contraceptive pill in spite of significantly elevated CBG. There was no relationship between saliva cortisol and progesterone levels, and it is unlikely that the increase in cortisol is due to displacement of cortisol from CBG by progesterone. Cortisol levels fell slowly postpartum over several days, making it improbable that the increase in cortisol is solely due to elevated CRH levels. It appears that increased free and total cortisol levels in pregnancy are related to resetting of the sensitivity of the hypothalamic-pituitary-adrenal axis and not merely to raised CBG, progesterone, or CRH levels.

Maternal plasma progesterone levels fall after rectal administration of estriol.

Maternal plasma unconjugated estriol (E3), progesterone (P), and estradiol (E2) levels were measured at 30-min intervals for 6 h after the rectal administration of a 100-mg E3 or placebo suppository to 28 pregnant women at term. Mean plasma unconjugated E3 levels showed a sustained rise approximately 50% above baseline levels 2 h after rectal E3 administration (P < 0.003). There was a simultaneous sustained fall of approximately 20% in mean plasma P levels (P < 0.05); the fall in mean P levels was greatest in the women who delivered within 48 h of E3 suppository administration (P < 0.05). There was no change in mean plasma E2 levels. This study demonstrates that a significant rapid increase in maternal circulating E3 levels can be obtained by the rectal administration of E3, and that this increase in maternal E3 levels is associated with a decrease in circulating P levels.

Hormone levels in the reproductive system of normospermic men and patients with oligospermia and varicocele.

The endocrine milieu on which spermatogenesis and sperm maturation mainly depend was evaluated quantitatively with simultaneous measurements of FSH, LH, PRL, testosterone, estrone, estradiol (E2), and sex hormone-binding globulin concentrations in spermatic venous plasma, antecubital plasma, seminal fluid, and wash fluid from vas deferens in 16 normospermic men and 24 oligospermic patients. Anesthesia and surgical stress caused a rise of only PRL and E2 (P less than 0.001-0.01). Mean FSH, LH, and PRL levels were comparable in antecubital and spermatic venous plasma, and antecubital values were higher in oligospermic patients for FSH and LH (P less than 0.05-0.001). Mean (+/- SD) T levels were similar for normospermic and oligospermic men in spermatic venous plasma (473 +/- 75 and 439 +/- 270 ng/ml), in antecubital plasma (6.5 +/- 1.3 and 6.6 +/- 1.8), and in seminal fluid (0.3 +/- 0.1 for both). Minute quantities of testosterone were detected in pooled wash fluid (0.08 ng). For E2, similar concentration gradients from high to low levels were found in normospermic and oligospermic men (spermatic venous plasma = 926 +/- 205 pg/ml and 1090 +/- 262; antecubital plasma = 31.0 +/- 12.0 and 28.4 +/- 1.9; seminal fluid = 14.3 +/- 2.3 and 12.0 + 2.8). Estrone was also high in spermatic venous and low in antecubital plasma but higher in seminal fluid than in antecubital plasma. Sex hormone-binding globulin levels were slightly though not significantly lower in spermatic venous (23 +/- 10 nmol/liter) than in antecubital plasma (28 +/- 6), but not measurable in seminal fluid. These results define important aspects of the endocrine milieu prevailing in the male reproductive tract and demonstrate a change of the relative activity of androgens and estrogens from the testis to the seminal fluid.

p107 is active in the nucleolus in non-dividing human granulosa lutein cells.

Cells are maintained in a quiescent state by members of the retinoblastoma protein family, pRb and p130. Both are phosphoproteins and hypophosphorylated forms of pRb and p130 bind and repress the activity of E2F transcription factors, thereby preventing entry into the cell cycle. Mitogenic stimulation causes activation of cyclin dependent kinases (cdk) that phosphorylate both pRb and p130, thereby releasing E2F factors which stimulate the transcription of a number of genes that are required for DNA synthesis and for regulating the cell cycle. In non-dividing cells, cdks are maintained in an inactive state by cdk inhibitor proteins such as p27(Kip1). The aim of our study was to determine how E2F complexes are regulated during the differentiation of human primary granulosa lutein cells (GLC) of the corpus luteum (CL). The CL is formed in the ovary after ovulation at the terminal stage of folliculogenesis after completion of maturation and differentiation of Graafian follicles. As shown by flow cytometry GLC are not dividing, being predominantly in the G(0)/G(1) phase of the cell cycle and, consistent with this, they contain the cdk inhibitor protein, p27(Kip1), but not E2F-1 which is normally expressed only in proliferating cells. The GLC do express E2F-4, hypophosphorylated pRb, p130 forms 1 and 2 and, surprisingly, hypophosphorylated p107. p107 is normally present only in dividing cells where it regulates E2F activity during the cell cycle. These forms of pRb, p130 as well as p107, together with E2F-4 are all active in that they can bind an E2F DNA-binding site in a pull-down assay. Immunocytochemistry shows that these proteins are expressed in almost all GLC but have different sub-cellular distribution: p107 is concentrated in nucleoli, while p130 and E2F-4 show relatively even nuclear and cytoplasmic distributions. Both pRb and p130 have been implicated previously in repressing E2F activity in many different cell types during cell cycle arrest in G(0)/G(1). We conclude that p107 is active in human primary GLC but its nucleolar localisation would suggest that it represses ribosomal RNA synthesis rather than E2F activity.

Fetal endocrine responses to prolonged reduced uterine blood flow are altered following bilateral sectioning of the carotid sinus and vagus nerves.

The present study examines the effect of carotid sinus/vagosympathetic denervation on fetal endocrine responses to prolonged reduced uterine blood flow (RUBF). Fetal sheep had vascular catheters inserted following bilateral sectioning of the carotid sinus and vagus nerves (denervated, n = 7) or sham denervation (intact, n = 7). Uterine blood flow was mechanically restricted at 126.1 +/- 0.7 days (mean +/- S.E.M.) for 24 h, decreasing arterial oxygen saturation by 47.3 +/- 2.6% (P < 0.01). Fetal plasma samples were obtained at -1, 3, 6, 12 and 24 h for subsequent analyses of arginine vasopressin (AVP), angiotensin II and catecholamines. The AVP response to prolonged RUBF was markedly attenuated in denervated fetuses (15.6 +/- 3.6 to 34.9 +/- 6.0 pg/ml) when compared with intact (10.0 +/- 1.4 to 127.3 +/- 28.4 pg/ml). In contrast, intact fetuses demonstrated no change in plasma angiotensin II concentrations with RUBF whereas denervated fetuses demonstrated a marked increase from 47.5 +/- 18.9 to 128.7 +/- 34.2 pg/ml. The norepinephrine and epinephrine responses to prolonged RUBF were attenuated in denervated fetuses (950.1 +/- 308.9 and 155.8 +/- 58.5 to 1268.3 +/- 474.6 and 290.6 +/- 160.2 pg/ml respectively) when compared with intact (1558.3 +/- 384.4 and 547.3 +/- 304.7 pg/ml to 3289.2 +/- 1219.8 and 896.8 +/- 467.8 pg/ml respectively). These results support a role for the peripheral chemoreceptors in mediating fetal endocrine responses to prolonged RUBF, which may in part lead to the altered cardiovascular responses observed in denervated fetuses under these conditions.

Effect of maternal nutrient restriction in early gestation on development of the hypothalamic-pituitary-adrenal axis in fetal sheep at 0.8-0.9 of gestation.

The fetal hypothalamic-pituitary-adrenal (HPA) axis has numerous key roles in development. Epidemiological data have linked adverse prenatal nutrition with altered organ development and increased incidence of disease in adult life. We studied HPA axis development in resting and stimulated states in late gestation fetal sheep, following 15% reduction in maternal nutritional intake over the first 70 days of gestation (dGA). Fetuses from control (C) and nutrient-restricted (R) ewes were chronically catheterised and response profiles for ACTH and cortisol were determined at 113-116 and 125-127 dGA after administration of corticotrophin releasing hormone (CRH) and arginine vasopressin (AVP). At 126-128 dGA cortisol profiles were also determined following ACTH administration. Basal ACTH and cortisol concentrations were not different between C and R fetuses. In R fetuses, ACTH response to CRH+AVP was significantly smaller at 113-116 dGA (P<0.01), and cortisol responses were smaller at both 113-116 dGA (P<0.01) and 125-127 dGA (P<0.0001). Cortisol response to ACTH was also smaller in R fetuses (P<0.001). We conclude that, in late gestation fetal sheep, pituitary and adrenal responsiveness is reduced following modest maternal nutrient restriction in early gestation.

Diurnal rhythm of testosterone induced by human chorionic gonadotrophin (hCG) therapy in isolated hypogonadotrophic hypogonadism: a comparison between subcutaneous and intramuscular hCG administration.

When human chorionic gonadotrophin (hCG) is used to stimulate testosterone synthesis and release in males with hypogonadotrophic hypogonadism, it is administered two or three times weekly by intramuscular injection. We have compared the pharmacokinetics of a twice weekly standard dose of hCG (5000 U) given for the first week by intramuscular injection and in the second week by self-administered subcutaneous injection. The patients studied had Kallmann's syndrome, isolated idiopathic hypogonadotrophic hypogonadism or post-traumatic isolated hypogonadotrophic hypogonadism. Salivary testosterone was collected twice daily at 08.00 h and 20.00 h, and serum testosterone was collected after 0, 24 h, 72 h, 120 h and 168 h each week. The cumulated serum and salivary testosterone levels were comparable on both intramuscular and subcutaneous hCG. In normal males there is diurnal variation in testosterone, with peak serum levels in the morning falling to a nadir in the evening. The exact nature and controlling factors of this circadian rhythm have not been established. In four of the subjects, the twice weekly hCG injections, either subcutaneous or intramuscular, produced a regular testosterone diurnal rhythm. The other four patients had fluctuations in testosterone but with no strict diurnal pattern. This study provides evidence that the luteinizing hormone-like action of hCG is necessary to prime the circadian rhythm but only a single bolus of hCG is sufficient to induce the rhythm in the absence of endogenous gonadotrophin production. In conclusion, self-administered subcutaneous hCG is safe and produces comparable levels of serum and salivary testosterone to that administered by the intramuscular route. Moreover, it was very well accepted by the patients and was preferred to conventional treatments. Human hCG in some patients with hypogonadotrophic hypogonadism produces normal physiological changes in daily testosterone levels.

Management of erectile dysfunction by combination therapy with testosterone and sildenafil in recipients of high-dose therapy for haematological malignancies.

Erectile dysfunction (ED) is a well recognised complication of bone marrow transplantation, which affects quality of life in adult patients. Although the major contributory factors include hypogonadism and psychogenic factors, the best treatment still remains to be established due to the complex aetiopathology of the condition. Here, we report our preliminary results in eight patients treated with testosterone replacement therapy and sildenafil. We studied eight male recipients of BMT aged 22-58 years, presenting with clinical features of hypogonadism, ED, diminished libido and ejaculatory disorders. ED was assessed clinically and by colour flow Doppler studies of the cavernosal vessels. Testicular function was assessed by testicular volume, FSH, LH and testosterone (T) measurements. Erectile performance, libido and ejaculatory function were determined by a structured interview. Patients had severe primary hypogonadism as evidenced by low mean testicular volume, elevated gonadotrophins and low normal mean testosterone levels compared with controls. All had Leydig cell insufficiency (LCI) with or without frank serum testosterone insufficiency. All except one had cavernosal arterial insufficiency. All patients received intramuscular injections of testosterone cypionate (250 mg 4 weekly) for 6 months and 50-100 mg of sildenafil orally, one to two times per week. All patients responded favourably as substantiated from the NIH consensus criteria. Our preliminary results suggest that this combined therapy is a safe and effective therapeutic approach in recipients of high-dose therapy presenting with ED after transplant.

Prospective study of pituitary-gonadal function to evaluate short-term effects of ablative chemotherapy or total body irradiation with autologous or allogenic marrow transplantation in post-menarcheal female patients.

Pituitary-gonadal (P-G) function was evaluated 0-3 months before and 3-4 months after bone marrow transplantation (BMT) in 15 post-menarcheal females aged 17-30 (21.6 +/- 0.34) years with haematological malignancies. All patients had evidence of gonadal insufficiency prior to BMT in that their basal and human menopausal gonadotrophin (HMG)-stimulated oestradiol (E2) levels were significantly lower than those of control subjects. The patients also had markedly higher basal FSH levels and exaggerated responses to 100 micrograms iv gonadotrophin release hormone bolus compared with those of control subjects. However, the conditioning regimens employed prior to BMT, i.e. cytotoxic chemotherapy (CT) and total body irradiation (TBI), acting either singly or in combination, caused further ovarian damage. As a result, their gonadotrophins rose further into the menopausal range. Their oestradiol secretion diminished and ovaries became almost unresponsive 3-4 months after BMT. Pelvic ultrasound undertaken in 5 patients before and after BMT demonstrated a reduction in ovarian size associated with follicular depletion. All patients developed menopausal symptoms and became amenorrhoeic during this period. Contrary to expectation, the hormonal changes occurring acutely were similar in patients undergoing radiation-based regimens and those conditioned with high-dose chemotherapy alone. Also, the severity of ovarian dysfunction appeared independent of age at transplantation, the nature of the conditioning-regimen or the type of transplant. Gonadotrophic, thyrotrophic, lactotrophic and adrenocorticotrophic secretions were unaffected. These data indicate that the ovary suffers an acute insult during short-term chemotherapy but the anterior pituitary gland retains its trophic hormone reserve and secretory capacity.

Germ cell failure and Leydig cell insufficiency in post-pubertal males after autologous bone marrow transplantation with BEAM for lymphoma.

Thirteen post-pubertal male patients aged 17-25 years were assessed for pituitary-gonadal function 0-3 months prior to and 2-3 months post-bone marrow transplantation for haematological malignancy. All patients had multiagent cytotoxic treatment prior to transplantation and 30% were found to have germ cell dysfunction with abnormal semen parameters before high-dose therapy indicating damage to the germinal epithelium. They also had evidence of reduced Leydig cell reserve even before transplantation. During transplantation all patients sustained sustained gonadal injury, the effect on their germ cells being more pronounced than on the Leydig cells. Fifty per cent had reduction in testicular volume and all had azoospermia 2-3 months post-transplantation. Our results indicate that short-term chemoradiotherapy causes profound damage to the germ cell compartment of the testis, with less severe damage to the Leydig cells, but no overt injury to the anterior pituitary gland. The changes appeared to be identical in patients conditioned with total body irradiation-based protocols and those who received only high-dose chemotherapy prior to bone marrow transplantation.

Partial hypopituitarism following total body irradiation in adult patients with haematological malignancy.

We present the endocrine parameters of two adult patients with partial hypopituitarism documented at 6 and 8 months after chemotherapy, single fraction total body irradiation (10.5 Gy) and autologous bone marrow transplantation. The hormone profiles demonstrate severe somatotroph insufficiency and impaired adrenocorticotroph secretory capacity, despite sparing of the gonadotroph compartment. We recommend stimulatory testing of hypothalamic-pituitary function from 3 months post-transplant, as basal hormonal concentrations may be equivocal, and supplementation may significantly improve quality of life.

Gynaecomastia with hypergonadotrophic hypogonadism and Leydig cell insufficiency in recipients of high-dose chemotherapy or chemo-radiotherapy.

Late side-effects of stem cell transplantation include hypogonadism with infertility and sexual dysfunction, but gynaecomastia is less well recognised. We report five cases of gynaecomastia with features of hypergonadotrophic hypogonadism (primary testicular failure), who received either a TBI/cyclophosphamide conditioned allograft (n = 3) or a BEAM autograft (n = 2). Patients receiving an allograft had gynaecomastia, Leydig cell insufficiency (LCI) diminished libido and erectile dysfunction. Surgery was required in one case, while in two cases the gynaecomastia resolved spontaneously after 6 months. Two patients also had gynaecomastia and sexual dysfunction, severe hypogonadism, very low testosterone levels and marked hyperprolactinaemia following autoBMT. Both responded well to testosterone replacement therapy (TRT). As a group, all patients had primary testicular failure and all except one, had LCI (compensated or frank). However, there was no correlation between the severity of gynaecomastia and the degree of endocrine dysfunction. This preliminary study is the first to suggest that gynaecomastia, due to primary hypogonadism and LCI, may be a significant complication of myeloablative conditioning therapy. Therefore gynaecomastia in BMT recipients must always be treated as a pathological entity as it may be the external manifestation of a complex endocrine pathology. It is a potentially treatable condition. Although spontaneously reversible, some patients may require TRT or even surgery. We recommend comprehensive endocrine testing in conjunction with a reproductive endocrinologist and prompt intervention to alleviate embarrassment and anxiety in afflicted BMT recipients.

Hypogonadotrophism fails to prevent severe testicular damage induced by total body irradiation in a patient with beta-thalassaemia major and acute lymphoblastic leukaemia.

Radiation and chemotherapeutic drugs for cancer produce prolonged and often irreversible gonadal damage. To determine whether total body irradiation (TBI)-induced gonadal damage can be prevented by suppression of pituitary gonadotrophin levels, we studied a patient with transfusion dependent homozygous beta-thalassaemia and acute lymphoblastic leukaemia (ALL) who underwent one-antigen mismatched related bone marrow transplantation (BMT). Our data showed that despite having hypogonadotrophic hypogonadism (HH) prior to BMT, the patient developed primary testicular failure following the procedure, indicating that hypogonadotrophism failed to offer protection against TBI-induced testicular damage in this patient. Although this is an interesting case report, no firm conclusions can be drawn from a single patient.

Germ cell damage and Leydig cell insufficiency in recipients of nonmyeloablative transplantation for haematological malignancies.

Most bone marrow transplant recipients are infertile due to reversible or irreversible testicular failure. However, little is known about the gonadotoxic potential of the newly introduced nonmyeloablative transplants. We undertook a 24-month longitudinal study in a cohort of 32 recipients of nonmyeloablative transplantation to test whether the combined regimen of fludarabine, melphalan and CAMPATH-1H can induce damage to germ cell (GC) and Leydig cell (LC) compartments. Testicular function was assessed immediately prior to transplantation and at four time points post-transplant to compare hormonal levels before and after the procedure. Two other groups treated with BEAM- and TBI-related regimes were also included in the study group for comparative purposes. GC function was assessed by measuring basal serum follicle stimulating hormone (FSH). LC function was assessed by measuring basal luteinising hormone (LH) and testosterone (T) levels. LC reserve was assessed by measuring the T/LH ratio. As a group, patients who received a non myeloablative transplant sustained severe damage to the GC compartment, as evident from a substantial elevation in the FSH level post-transplant (12 IU/l vs 18.4 IU/l, P<0.001). Similar to the GC injury, patients as a group sustained significant damage to the LC compartment following the transplant (5.4 IU/l vs 9.6 IU/l, P<0.001). In general, patients had reduced LC reserve post-BMT, as evident from a diminished T/LH ratio (2.6 pretransplant vs 1.6 post-transplant P=0.05). Patients who received a nonmyeloablative transplant had a similar effect on the GC and LC compartments compared to those who had a BEAM autograft. On the other hand, patients who received a TBI-based transplant sustained more damage to their GC and LC compartments compared to those who received a nonmyeloblative transplant; however, this was not statistically significant (P=0.09). Our data suggest that this type of regimen is potentially gonadotoxic and consideration should be given to fertility counselling and testosterone replacement therapy post-transplant.

Cavernosal arterial insufficiency is a major component of erectile dysfunction in some recipients of high-dose chemotherapy/chemo-radiotherapy for haematological malignancies.

We studied 24 male patients aged 26-62 years (median 41) prospectively presenting over a 5 year period with clinical features of hypogonadism and erectile dysfunction (ED), who had been treated with autologous or allogeneic bone marrow/stem cell transplant for a variety of haematological malignancies and had received either high-dose chemotherapy or high-dose chemotherapy combined with total body irradiation (TBI). Ten healthy adult controls (aged 35-50 years) were also studied. Erectile dysfunction (ED) was assessed clinically and by colour flow Doppler studies of the cavernosal vessels. Testicular function was assessed by testicular volume including orchidometry, FSH, LH and testosterone measurements. Libido and ejaculatory function were also recorded. Patients had severe hypogonadism as evidenced by low mean testicular volume (7.0 +/- 2.4 ml vs 20 +/- 2.0 ml; P < 0.001), elevated gonadotrophins (FSH = 18.54 +/- 7.61 vs 5 IU/l (P < 0.001); LH = 8.02 +/- 2.89 vs 3. 9 IU/l (P < 0.001)) and low normal mean testosterone levels (16.4 nmol/l +/- 9.1 vs 22.4 nmol/l (P < 0.5)). Cavernosal arterial insufficiency was found in 11/14 of TBI-treated and in 3/10 HDC-treated patients, indicative of vasculogenic damage to corpora cavernosal vessels. Patients were given a therapeutic trial with testosterone replacement therapy (TRT). Those who had diminished libido had a marked improvement in their symptoms but the effect of TRT on ED was equivocal. In conclusion, this is the first report to show vasculogenic insufficiency in patients with haematological malignancies treated by BMT. Although hypogonadism can account for diminished libido, arteriogenic insufficiency is likely to be an important factor accounting for ED in these patients, especially those treated by TBI. We recommend a comprehensive assessment including endocrine profile and colour flow Doppler study in formulating the best management plan in recipients of high-dose therapy presenting after transplant with ED.

Patterns of Leydig cell insufficiency in adult males following bone marrow transplantation for haematological malignancies.

Gonadal and sexual function are key to quality of life following bone marrow transplantation (BMT), but no large studies have been published on Leydig cell (LC) function in adults. LC insufficiency (LCI) can cause premature andropause with its consequences including sexual morbidity from diminished libido and erectile dysfunction (ED). In addition, LCI can result in generalised fatigue and even osteopenia. We reviewed gonadal function pre-transplant (immediately prior to BMT) and at 3-18 months post BMT in 117 patients who underwent BMT for a variety of haematological malignancies. The patients presented with variable degrees of symptoms of LCI, such as fatigue, diminished sex drive and libido or ED. The results suggest that the patients sustained severe gonadal damage to both their germ cells (GC) as well as the LC compartment (P < 0.001). We characterised two distinct functional subsets of LC insufficiency: Type I: compensated type with high LH and normal T levels and low T/LH ratio: (n = 102); and type II: uncompensated type (premature andropause) with high LH and low testosterone levels with low T/LH ratio (n = 15). Although type II patients had more severe LC damage than type I, patients in both groups were symptomatic. We recommend that symptomatic patients in both groups may benefit from a therapeutic trial with testosterone replacement treatment (TRT) for 3-6 months.

Pharmacokinetics of sex steroids in patients with beta thalassaemia major.

AIMS: To assess the pharmacokinetics of oral, intramuscular, or transdermal hormone replacement in patients with beta thalassaemia major. METHODS: Oral (testosterone undecanoate 40 mg) and intramuscular (testosterone propionate 15 mg, phenylpropionate 30 mg, isocaproate 30 mg and decanoate 50 mg) testosterone and transdermal (17 beta oestradiol 25 micrograms and 50 micrograms) oestradiol were evaluated in 21 male (16-29 years) and 11 female (19-26 years) patients with beta thalassaemia major and various forms of hypogonadism. RESULTS: In male patients given oral testosterone, peak testosterone concentrations were observed either two to four hours or seven hours after administration; intramuscular testosterone produced peak values seven days after injection. Transdermal 17 beta oestradiol given to female patients produced a biphasic pattern with an initial peak concentration occurring at 36 hours and a secondary rise at 84 hours. CONCLUSIONS: The results indicate that oral androgens should be given twice daily in cases of hypogonadism, and where growth is incomplete, lower than recommended doses. If intramuscular testosterone is used, smaller doses of 10-25 mg should be given every one to two weeks. Transdermal administration of 25-50 micrograms 17 beta oestradiol generally produces a plasma E2 value in the early to mid-follicular phase range (100-300 pmol/l). This is appropriate in adults but excessive for prepubertal girls. Diffuse iron infiltration of tissues does not seem to interfere with the absorption of androgens and oestrogens from the gut, muscle, or skin.

Induction of ovarian function by using short-term human menopausal gonadotrophin in patients with ovarian failure following cytotoxic chemotherapy for haematological malignancy.

Currently no treatment has proved successful in inducing ovarian steroidogenic and/or gametogenic recovery in patients with haematological malignancies treated by cytotoxic chemotherapy once biochemical failure becomes manifest i.e., when FSH levels exceed 40 IU/L. This paper reports two such cases with classical biochemical ovarian failure in which ovarian function was induced by brief stimulation with Human Menopausal Gonadotrophin (HMG).