Andrology: Effect of growth hormone administration on circulating levels of luteinizing hormone, follicle stimulating hormone and testosterone in normal healthy men

A new area of growth hormone (GH) therapy in adults is the treatmentof infertility. The aim of this study was to evaluate the effectsof pharmacological GH administration on the secretion of pituitaryand gonadal hormones in normal men. Eight healthy men, 23–32years of age (mean 28.1 years), with a normal body mass indexwere studied in a double-blind, placebo-controlled crossoverdesign. All participants had a normal semen analysis beforeentering the study. Each participant was treated with placeboand GH (12/IU/day, Norditropin; Novo Nordisk, Denmark) duringtwo different 14-day periods, separated by a 6 week washoutperiod. Administration of GH for 14 days resulted in a significantincrease in serum insulin-like growth factor I (IGF-I; P <0.01) but no changes occurred in IGF-I values during placebotreatment. The concentrations of follicle stimulating hormoneand luteinizing hormone displayed no change during the two periodsand did not differ between the GH treatment period and the placeboperiod. The concentration of testosterone was unchanged duringthe placebo/GH periods and there was no difference between theGH treatment period and the placebo period. We conclude thatGH treatment for 14 days in normal healthy men does not affectgonadotrophin or testosterone patterns.     

Effect of follicle stimulating hormone treatment on the pituitary response to luteinizing hormone-releasing hormone in post-menopausal women

To study the role of exogenous follicle stimulating hormone(FSH) in the attenuation of luteinizing hormone (LH) responseto luteinizing hormone-releasing hormone (LHRH) during ovulationinduction in women, 10 healthy post-menopausal women were treatedwith FSH (225 IU/day) for 5 days and normal saline (2 ml/day)for another 5 days. The two regimens were given consecutivelyin a 10 day experiment. The regimen for the first 5 days wasrandomly chosen and was given to the women in an alternate way.The response of LH to an i.v. injection of 10 µg LHRHwas investigated twice on day 1 (i.e. before the onset of treatmentand 12 h later) and once on days 2, 5 and 10 of the experiment(0900 h). Basal FSH and LH values before the onset of treatmenton day 1 were similar in the five women who started with thesaline and the five who started with the FSH regimen. BasalFSH values increased significantly during treatment with FSH,while LH and oestradiol values remained unchanged throught thewhole experiment. LH increment 30 min post –LHRH did notchange significantly either during the first 24 h or duringthe whole experiment regardless of the starting regimen. Theseresults demonstrate that in post-menopausal women the responseof LH to LHRH is not affected by exogenous administration ofFSH. It is suggested that exogenous FSH does not show activitieson gonadotrophin secretion similar to those ascribed to a gonadotrophinsecretion similar to those ascribed to a gonadotrophin surgeattenuating factor.     

The effect of recombinant follicle stimulating hormone (Gonal-F) on endogenous luteinizing hormone secretion in women

Parenteral administration of follicle stimulating hormone (FSH) has been shown to lower luteinizing hormone (LH) concentrations in women undergoing ovulation induction. This study was designed to explore the physiological mechanism of this effect. Seven healthy women were recruited into a double-blind placebo-controlled study. LH secretion, after the administration of variable i.v. boluses (37.5, 75 and 150 IU) of recombinant FSH (Gonal-F), was evaluated. LH was measured at 10 min intervals for 2 h before and 4 h after the FSH/placebo infusion. LH pulse frequency and amplitude were evaluated and there was no significant difference between control and trial cycles for each subject. A linear regression analysis revealed that in the group receiving 150 IU FSH, the mean plasma LH concentration decreased significantly due to a reduction tonic LH secretion. This could be a result of the suppression of secretion or an alteration of clearance. This decrease was not seen in the other dosage groups, revealing that above a dosage threshold, FSH reduced non-pulsatile LH secretion. Therefore the effect of FSH in this study exposed the likely presence of two components of LH concentration: an FSH-sensitive, non-pulsatile tonic secretion and a gonadotrophin-releasing hormone-stimulated, pulsatile release that is unaffected by FSH. Although an indirect effect involving ovarian regulation is not excluded, the rapidity of the effect suggests that FSH acts directly on the pituitary gland.      

The value of basal serum follicle stimulating hormone, luteinizing hormone and oestradiol concentrations following pituitary down-regulation in predicting ovarian response to stimulation with highly purified follicle stimulating hormone.

The value of gonadotrophin and oestradiol concentrations following pituitary down-regulation with leuprolide acetate in predicting ovarian response to stimulation was evaluated in three groups of women undergoing ovarian stimulation for in-vitro fertilization with highly purified follicle stimulating hormone (FSH). Leuprolide acetate was started in the midluteal phase, and either stopped at menses (IVF-SL group, n = 3), or continued throughout stimulation (IVF-LL group, n = 38; oocyte donors, n = 58). Ovarian stimulation was started on cycle day 3, after blood was drawn for down-regulated FSH, luteinizing hormone (LH) and oestradiol. Higher down-regulated LH was predictive of higher oestradiol on day 5 of stimulation in both IVF groups, and of need for fewer ampoules in the IVF-LL group, but not of oestradiol on day of human chorionic gonadotrophin (HCG) administration or number of oocytes retrieved. Higher FSH after down-regulation predicted yield of fewer oocytes in the donor and IVF-LL groups, and higher oestradiol on day 5 of stimulation, need for fewer ampoules and a shorter duration of therapy in both IVF groups. Higher oestradiol after down-regulation was associated with higher oestradiol on day 5 of stimulation and on day of HCG administration, a shorter duration of therapy and need for fewer ampoules in all groups. Whereas these results do not ascribe any predictive significance to LH, they suggest that oestradiol and FSH concentrations after down-regulation are predictive of the pattern of ovarian response to stimulation and of oocyte yield.     

Current concepts of the roles of follicle stimulating hormone and luteinizing hormone in folliculogenesis

Around 400 follicles sequentially mature and ovulate duringan average women‘s reproductive lifetime. From birth tothe menopause, the other 99.98% of her follicles begin developmentbut never complete it. Instead they default to atresia due toinadequate stimulation by follicle stimulating hormone (FSH).Follicular growth to the stage of antrum formation (0.25 mmdiameter) is independent of gonadotrophic stimulation. Antrumformation and further growth to the stage at which folliclesbecome potentially able to begin pre-ovulatory development (2–5mm diameter) require tonic stimulation by FSH. Before onsetof puberty, blood concentrations of FSH do not rise sufficientlyto sustain development beyond this stage, therefore all antralfollicles become atretic. After puberty, as each menstrual cyclebegins, FSH concentrations rise beyond a critical ‘threshold’and multiple follicles are recruited to begin pre-ovulatorydevelopment. Due to increases in its responsiveness to FSH andluteinizing hormone (LH), one of these follicles becomes selectedto ovulate while the remainder become atretic. At mid-follicularphase, the dominant follicle reaches 10 mm in diameter and increasinglysynthesizes oestradiol. Tonic stimulation by FSH and LH, underpinnedby local paracrine signalling, maintains oestrogen secretionby the dominant follicle, which grows to 20 mm in diameter beforeit ovulates in response to the mid-cycle LH surge. The development-relatedresponse to LH shown by the pre-ovulatory follicle raises thepossibility that exogenous LH might be used as an adjunct totherapy with exogenous FSH in clinical ovulation induction regimenswhere the aim is to induce monovulation.     

Serum concentrations of follicle stimulating hormone may predict premature ovarian failure in FRAXA premutation women.

It is now recognized that female carriers of fragile X premutations are at increased risk of premature ovarian failure. We have studied 51 premenopausal women from fragile X families, to determine whether premutation carriers have variations in the hormonal markers of menopause, compared to full mutations and controls. We found a significant increase in serum follicle stimulating hormone in premutation carriers, suggesting that as a group they will enter menopause before full mutation carriers and unaffected controls. These results have important implications for fertility in these women.     

Annual patterns of luteinizing hormone, follicle stimulating hormone, testosterone and inhibin in normal men

Reproductive functions in most animals demonstrate seasonalfluctuations that allow young to be born at a time of the yearfavourable for their survival. Whether there is a seasonal changein the human reproductive system is unclear. In the presentstudy, we measured serum concentrations of luteinizing hormone,follicle stimulating hormone, testosterone and inhibin in thesame 16 normal men sampled monthly for 1 year. A statisticallysignificant increase in all four measured hormones was foundin June, with a nadir in August. Our findings suggest that acircannual rhythm of gonadotrophins and testicular hormonesexists in normal men. The mechanism leading to this rhythm andthe importance of the rhythm in human biology are unknown.     

Effect of antagonists of dopamine and opiates on the basal and GnRH-induced secretion of luteinizing hormone, follicle stimulating hormone and prolactin during lactational amenorrhoea in breastfeeding women

The role of dopamine and opiates in the suckling-induced suppressionof gonadotrophin secretion and prolactin release was investigatedduring lactational amenorrhoea in fully breastfeeding womenat 12 weeks post-partum. A total of 26 women, 20 using non-steroidalmethods of contraception and six using the progestogen-onlypill, Noriday (POP), breastfed their babies on demand at a frequencyof 3.6 ± 0.2 suckling episodes during the 8 h study periodwhile blood samples were collected at 10-min intervals. Fivehours after the start of sampling six women were given the dopamineantagonist metoclopramide (10 mg, i.m.) while four women receivedsaline. In a second experiment, six women using nonsteroidalcontraception and three women on the POP received an i.v. infusionof the opiate antagonist naloxone (1.6 mg/h) for 2 h, whilefour women using non-steroidal contraception and three womenon the POP were infused with saline. Two hours after the i.m.injection or start of infusion all women were given an i.v.injection of 10 µg gonadotrophin releasing hormone (GnRH)and samples were collected for a further 1 h. All samples wereassayed for luteinizing hormone (LH), follicle stimulating hormone(FSH) and prolactin. Plasma concentrations of oestradiol were<60 pmol/l in all women and they remained amenorrhoeic forat least 10 weeks after the study. Pulsatile release of LH wasonly observed over the 5 h pre-treatment period in 10 of the20 non-steroid taking women (1–3 pulses/5 h), and in oneof the six women (1 pulse/5 h) on POP. Treatment with metoclopramidecaused a substantial (29-fold) increase in prolactin over baseline,7.4 times the maximum released in response to suckling. Therewas no effect of metoclopramide on the pattern of release ofLH or FSH or the response to GnRH. Infusion of naloxone in womenusing either non-steroidal contraceptives or progestogen-onlypill did not affect prolactin release. Naloxone infusion didnot affect LH or FSH in women using nonsteroidal contraceptives,but caused a small but significant (P < 0.05) increase inboth LH and FSH in women taking the progestogen-only pill. Therewas a significantly greater release of LH and FSH after GnRHin all women after naloxone infusion. These results in breastfeedingwomen during lactational amenorrhoea confirmed that sucklingsuppresses the pulsatile release of LH but not through a dopaminergicpathway, showed that prolactin remains under dopaminergic controlduring human lactation, but suckling does not appear to affectprolactin secretion via an opiate pathway and indicated onlya minor, if any, role for opiates in the sucklinginduced suppressionof GnRH/gonadotrophin secretion but a potential, previouslyunreported, effect of opiates in reducing pituitary responsivenessto GnRH.     

Human prolactin release induced by follicle stimulating hormone, luteinizing hormone and human chorionic gonadotrophin

Plasma prolactin levels rise in stimulated cycles. To clarifythe effects of gonadotrophin on the lactotrophs, three studieswere performed. First, plasma concentrations of prolactin duringclomiphene citrate (CC)-human menopausal gonadotrophin (HMG)-humanchononic gonadotrophin (HCG) treatment of women enrolled forin-vitro fertilization (IYF) were compared with those duringHMG-HCG administration while under pituitary suppression witha gonadotrophin releasing hormone (GnRH) analogue (buserelin).Women suppressed with buserelin had higher basal levels of PRLin plasma (14.4 ± 4.3 nglml versus 6.9 ± 1.4 ng/ml,P<0.001). Only buserelin-suppressed women showed a significantrise in plasma prolactin before HCG administration, while bothpatient groups had marked prolactin peaks after HCG injection.This peak was higher in the buserelin group (71.9 ± 50.7ng/ml versus 52.6 ± 29.7 ng/ml). The second study showedthat plasma levels of prolactin of 6 post- menopausal womenwere significantly increased 48 h after an injection of 5000IU HCG, i.m. (24.9 ± 17.4 ng/ml versus 12.4 ±6.2 ng/ml P<0.05). Third, plasma prolactin was studied in5 women over 30 days after surgical castration. An upward trendwas observed similar to that of endogenous gonadotrophin, withthe change in prolactin values closely correlating with thechange in concentrations of follicule stimulating hormone (P<0.005).All these findings suggest that human gonadotrophins stimulatelactotrophs.     

Recombinant follicle stimulating hormone stimulation in poor responders with normal basal concentrations of follicle stimulating hormone and oestradiol: improved reproductive outcome.

A total of 30 young infertile patients who exhibited a poor response in two previous consecutive cycles, despite having normal basal follicle stimulating hormone (FSH) and oestradiol concentrations, were invited to participate in a prospective randomized study comparing the clinical efficacy of recombinant (rFSH) and urinary (uFSH) follicle stimulating hormone. An evaluation of the total dose used (3800 IU versus 4600 IU, P < 0.05) and duration of treatment (10.2 days versus 13.2 days, P < 0.05) showed a significantly shorter treatment period as well as a significantly lower total dose of FSH required to induce ovulation successfully in the group of patients treated with rFSH. Significantly more oocytes (7.2 versus 5. 6, P < 0.05) as well as mature oocytes (5.9 versus 3.2, P < 0.01) were retrieved after rFSH treatment. In addition, significantly more good quality embryos were obtained (3.4 versus 1.8, P < 0.05) in the group of patients treated with rFSH and, as a result, higher pregnancy (33 versus 7%, P < 0.01) and implantation (16 versus 3%, P < 0.01) rates were achieved in these patients. It is concluded that rFSH is more effective than uFSH in inducing multifollicular development and achieving pregnancy in young low responders.     

Effect of profound suppression of luteinizing hormone during treatment with gonadotrophin-releasing hormone analogue and purified follicle stimulating hormone upon development of cryopreserved embryos

In response to previously published evidence from monkeys, this study examined the influence of the degree of luteinizing hormone (LH) suppression during the follicular phase of the stimulation cycle, upon cryopreserved embryo survival and development. The LH concentration of the mid-follicular phase was assessed in 250 in-vitro fertilization (IVF) cycles treated with gonadotrophin-releasing hormone analogue (GnRHa) and either purified follicle stimulating hormone (FSH) or human menopausal gonadotrophin (HMG), and was related to the performance of cryopreserved embryos in 351 subsequent embryo transfer cycles. Rates of embryo survival, embryo development rates, implantation rates, and pregnancy rates were examined with respect to the LH concentration recorded in the mid-follicular phase. In contrast to experimental evidence from other primates, there was no significant influence of the follicular phase LH concentration upon any of the parameters examined.      

The effects of a gonadotrophin-releasing hormone agonist on treatment with low dose follicle stimulating hormone in polycystic ovary syndrome

The objective of this study was to investigate whether the incidenceof monofollicular growth during stimulation with low dose folliclestimulating hormone (FSH) changes when adjuvant gonadotrophin-releasinghormone agonist (GnRHa) pre-treatment is administered in polycysticovary syndrome (PCOS). One group of patients (group 1) sufferingfrom clomiphene resistant PCOS was stimulated with low doseFSH. The results were compared with those from another groupof similar patients (group 2) subsequently stimulated with lowdose FSH combined with GnRHa. In group 1 15 patients had 39stimulation cycles performed; in group 2 13 patients had 33stimulation cycles performed. In group 1 44% of cycles weremonofollicular, whilst the corresponding figure in group 2 was14% (P = 0.04). Evidence was found for postponed atresia ingroup 2. In both groups 1 and 2 interindividual and intra-individualvariability of the FSH dose inducing follicular growth wereobserved. We concluded that during the use of GnRHa, stimulationwith low dose FSH less frequently resulted in monofolliculargrowth, possibly due to postponed atresia. Furthermore, theuse of GnRHa does not abolish the inter- and intra-individualvariability of the FSH dose inducing ongoing follicular growth.     

Utility of follicle stimulating hormone (FSH), luteinizing hormone (LH), oestradiol and FSH:LH ratio in predicting reproductive age in normal women

The relative efficacy of follicle stimulating hormone (FSH), luteinizing hormone (LH), FSH:LH ratio and oestradiol is evaluated as a predictor of ovarian reserve (reproductive age) in normal women. Serum levels of FSH, LH, oestradiol and FSH:LH ratios were measured during menstrual cycle days 1-4 in younger (20-25 years; n = 23) and older (40- 45 years; n = 32) reproductive age women with regular menstruation and normal reproductive function. On days 1-4, mean levels of FSH, oestradiol and FSH:LH ratios were significantly higher in older compared with younger women. FSH increased in concentration across cycle days in both age groups. A significantly lower LH value in younger versus older women was found only on day 1. Oestradiol showed no change across days in the younger group, but increased significantly from day 1 to day 4 in the older group. FSH values on days 1 or 2 were the best single predictor of age differences. However, the best prediction of age differences was obtained by using the combination of FSH and LH (as opposed to the FSH:LH ratio) on day 1 of the menstrual cycle.      

The significance of elevated basal follicle stimulating hormone in regularly menstruating infertile women

Elevated plasma follicle stimulating hormone (FSH) during thereproductive life is an early manifestation of ovarian ageing.The presence of elevated basal FSH in young, regularly menstruatingwomen may represent a stage of menopausal transition consequenton premature ovarian failure. A total of 48 regularly menstruating,infertile women aged <40 years, with high FSH and aged-matchedcontrols with normal FSH underwent detailed monitoring of endocrineand follicle growth during one complete menstrual cycle. Duringthe same cycle, detailed immunological screening was performedand the epidemiological features of all subjects were also reviewed.Subjects in the high FSH group had significantly higher basalFSH, luteinizing hormone (LH) and follicular phase LH concentrations.Despite their normal preovulatory oestradiol production, thehigh FSH group showed significantly slower follicular growth,smaller follicle diameter and lower luteal phase salivary progesterone.All these features have been described in older women duringtheir menopausal transition. In addition, the prevalence ofautoimmune antibodies was significantly higher in the high FSHgroup. This study suggests that infertile women with elevatedFSH are in their perimenopause despite having regular ovulatoryand apparently normal cycles. An autoimmune basis is suggestedas a factor underlying their premature ovarian failure. Furtherendocrinological and auto-immunological follow-up is recommended.     

A protocol using a low dose of gonadotrophin-releasing hormone agonist might be the best protocol for patients with high follicle stimulating hormone concentrations on day 3

We studied 98 in-vitro fertilization (IVF) patients with a highbasal follicle stimulating hormone (FSH;>6.5 IU/I) concentrationon day 3 who were treated with a low dose gonadotrophin-releasinghormone agonist (GnRHa) protocol and who had received in theprevious 6 months a long protocol with GnRHa in a depot formula.The evaluation was made using the previous IVF cycle of thesame patient as a control. The mean ± SD age of the patientswas 34.1 ± 4.2 years. The use of a low dose agonist protocolended with significantly less ampoules (37.5 versus 46.1), ashorter duration of stimulation (10.7 versus 12.3 days), a higheroestradiol concentration on day 8 (1068 versus 495 pg/ml), ahigher number of mature oocytes (5.9 versus 4.4) and a highernumber of good quality embryos (3.3 versus 2.3). The cancellationrate was lower (11 versus 24%). A GnRHa low dose protocol maybe the protocol of choice for patients with high FSH concentrationson day 3. Larger randomized studies are needed to confirm thesedata.     

Endocrinology: Insulin-like growth factor-I stimulated growth and progesterone production by granulosa--lutein cells. Lack of interaction with physiological concentrations of luteinizing hormone and follicle stimulating hormone

This study examined the effect of physiological concentrationsof insulin-like growth factor-I (IGF-I), follicle stimulatinghormone (FSH) and luteinizing hormone (LH) alone and in combinationon growth and progesterone production by human granulosa —lutein cells. Granulosa—lutein cells were obtained frompatients (n > 5) undergoing in-vitro fertilization (IVF)or gamete intra-Fallopian transfer (GIFT) treatment. Cells werecultured for 2 and 4 days in the presence of physiological concentrationsof human LH (code 68/40, 5IU/1), FSH (code 83/575, 20IU/1),or IGF-I (30 ng/ml) alone and in combination. Medium was changedevery 2 days. No change in cell number (relative to each patient'sown control) was observed after treatment with FSH or LH aloneor in combination at any time. IGF-I alone produced a 117 ±8% and 176 ± 15% (mean ± SEM, n = 5) increasein cell number after 2 and 4 days respectively. This increasewas unaffected by the addition of LH or FSH at any time. Basalprogesterone secretion was variable (1633, 975–2409 nmol/l,median and interquartile range, day 2) and decreased with timein culture (564, 375–1089 nmol/l, day 4). After 2 daysculture progesterone output increased by 116 ± 5% ofcontrol in response to LH and 153 ± 13% (mean ±SEM, n = 5) of control in response to IGF-I. After 4 days, LHand IGF-I stimulated progesterone levels by 279 ± 52%and 264 ± 37% (mean ± SEM, n = 5) respectively.IGF-I stimulated progesterone output was unaffected by the additionof LH or FSH at any time. FSH alone had no effect on progesteroneoutput and did not enhance the stimulation by LH. We concludefirstly that IGF-I stimulates the growth of granulosa—luteincells but this growth is unaffected by LH or FSH; secondly thatprogesterone secretion is stimulated by LH but that seen withIGF-I is secondary to an increase in cell number; thirdly thatFSH and LH do not synergize with IGF-I with regard to progesteronesecretion, and lastly that FSH does not stimulate progesteronesecretion or growth.     

The 24 h pattern of pulsatile luteinizing hormone, follicle stimulating hormone and prolactin release during the first 8 weeks of lactational amenorrhoea in breastfeeding women.

In women, breastfeeding results in a variable period of ovarian inactivity which is apparently related to suppression of the normal pulsatile release of luteinizing hormone (LH). However, pulse profiles had only been studied during the daytime. Since resumption of pulsatile LH secretion during puberty is initiated at night, the present study determined the pattern of pulsatile LH secretion in relation to that of follicle stimulating hormone (FSH) and prolactin, and suckling and ovarian activity at 4 and 8 weeks postpartum in 20 fully breastfeeding women with lactational amenorrhoea. Blood samples were withdrawn at 10 min intervals for 24 h from 0900 h to 0900 h at either 4 weeks (n = 9) or 8 weeks (n = 11) postpartum, while the mothers and babies continued their normal pattern of suckling activity. At 4 weeks postpartum, no LH pulses occurred over 24 h in six of the nine women while one (n = 1) or two (n = 2) LH pulses occurred in three of the nine women. In contrast, LH pulses were present in nine of the 11 women at 8 weeks postpartum. The pulse frequency varied considerably from two to eight pulses over the 24 h and there was no influence of the time of day or sleep on the time of the pulse release. Lactational amenorrhoea was maintained for at least 10 weeks afterwards and there was no relationship between the time of resumption of ovarian activity and the presence or absence of pulsatile LH secretion at 4 or 8 weeks postpartum.(ABSTRACT TRUNCATED AT 250 WORDS)