Low FSH Research Articles

The role of FSH in castration-induced adipogenesis: Highlighting differences between orchiectomy, GNRH agonists, and antagonists.

e16011 Background: Androgen deprivation therapy (ADT) results in weight gain and development of the metabolic syndrome. Inspired by the observation that adiposity accompanies the incremental increase in serum FSH levels in menopause, we hypothesized that GNRH antagonist which lower FSH levels will associate with reduced adiposity as compared to GNRH analogues and orchiectomy. Methods: 3T3-L1 fibroblasts differentiation into adipocytes and intracellular lipid accumulation were examined in the presence of escalating FSH doses (0-1000 IU/L) in charcoal stripped FCS supplemented medium to simulate castration. Cellular lipogenesis was assessed by image analysis (oil red staining) and by immunoblotting for fatty acid synthase (FAS) expression. In vivo, 6-week old C57Bl/6 male mice (n=30) were divided to receive either: orchiectomy + vehicle, sham procedure + vehicle, orchiectomy + GNRH antagonist (degarelix 50 mg/kg in vehicle), sham + degarelix, orchiectomy + GNRH analogue (enantone 2 mg/kg in vehicle), or sham + enantone. Serum testosterone, LH and FSH levels and differences in animal weight, visceral fat mass (VFm) and liver lipogenesis (oil red staining) were determined following sacrifice at 6 weeks. BMI was measured as weight (gr) divided by the distance between the tail root and the lower incisors (cm2). Results: The mean lowest and highest serum FSH levels were recorded in mice treated with Degarelix vs. orchiectomy (0.43 and 0.935 mIU/mL resp,) and the mean lowest and highest serum testosterone levels were in mice treated with orchiectomy+degarelix vs. sham control (0.12 and 13.1 ng/ml resp). Mice treated with degarelix had a significantly lower BMI compared to enantone (p=0.02). VFm (perirenal fat weight) was significantly lower (p=0.035) in mice castrated by degarelix (mean 0.38gr) as compared to enantone(mean 0.47gr)). Addition of degarelix or enanton to orchiectomy increased the differences in VFm and BMI between the two groups (0.12gr vs. 0.47gr and 3.73 vs. 4.29 gr/cm2 resp.) In vitro, FSH increased lipid accumulation and FAS expression in 3T3-L1 cells. Conclusions: FSH level elevation following castration promotes fat accumulation and weight gain in preclinical models.

Drilling ovarien par fertiloscopie : faisabilité, résultats et valeurs prédictives

ObjectivesThe aims of this study were to assess the effectiveness of the ovarian drilling, compare the techniques by fertiloscopy or by laparoscopy, and search for prognostic factors of success. Patients and methodsThis retrospective study focused on 154 ovarian drilling carried out between June 1998 and December 2010 where the drilling has been proposed after failure of the clomifene and before stimulation by FSH among PCOS patients. ResultsThe post-drilling ovulation rate is 62%. The spontaneous on-going pregnancy rate is 31% and the total pregnancy rate scalable including secondary stimulation is 58%. No significant difference was found between laparoscopy and the fertiloscopy. The peroperative complications in fertiloscopy were more frequent but without consequences and 20% of the fertiloscopy had to be converted to laparoscopy, half of them for complications and half of them for technical difficulties. The only found preoperative predictors of success are an euthyroidy that increases the chances of pregnancy in general (including the side stimulation) and a lower FSH levels. However, it appears that the chances of pregnancy in FSH stimulation are dramatically decreased if the drilling did not induce ovulation versus the cases where it induced ovulation but no pregnancy (28.8% versus 58.1%, P<0.003). Discussion and conclusionFertiloscopy results are comparable with those of laparoscopy, which suggests an advantage to this technique in terms of cost, comfort, and length of hospital stay. No usable in practice patient selection criteria could be highlighted. The study suggests that the absence of ovulation after drilling may be a direct indication for IVF.

Serum sex steroid levels and longitudinal changes in bone density in relation to the final menstrual period.

The associations of serum sex steroid and FSH levels with change of bone mineral density (BMD) across the complete menopausal transition are incompletely understood. The objective of the study was to examine the associations of annual serum levels of FSH, estradiol (E2), T, and SHBG with the rates of bone loss in 3 phases: pretransmenopausal [baseline to 1 year before the final menstrual period (FMP)], transmenopausal (1 year before to 2 years after the FMP), later postmenopausal (≥ 2 years after the FMP). The design of the study was a repeated-measures, mixed-effects regression. This was a community-based observational study, with a 10-year follow-up. A total of 720 participants of the Study of Women's Health Across the Nation Bone Study participated in the study. Annualized lumbar spine (LS) and femoral neck (FN) BMD decline was measured. The mean annual change in BMD was slowest in pretransmenopause (0.27%/year in FN) and fastest in transmenopause (2.16%/year in LS). In the pretransmenopausal phase, for every doubling of FSH level, LS BMD change was faster by -0.32%/year (P < .0001). In the transmenopausal phase, for every doubling of FSH level, LS BMD change was -0.35%/year faster (P < .0001); for every doubling of SHBG level, LS BMD change was -0.36%/year faster (P < .0001). In the later postmenopausal phase, for each doubling of the E2 level, the LS BMD change was slower by +0.26%/year (P = .049); for each SHBG doubling, the LS BMD change was 0.21%/year slower (P = .048). The FN associations were weaker and inconsistent. Higher E2 levels and lower FSH levels were associated with lower rates of LS bone loss in some but not all menopausal transition phases.

Peripubertal changes in circulating antimüllerian hormone levels in girls

ObjectiveTo identify correlates and longitudinal changes in circulating antimüllerian hormone (AMH) levels as a marker of ovarian primordial follicle recruitment in normal peripubertal girls.DesignObservational study using mixed longitudinal and cross-sectional analyses.SettingNot applicable.Patient(s)Unselected girls assessed at ages 7–11 years.Intervention(s)None.Main Outcome Measure(s)AMH, inhibin B, and FSH levels were analyzed in blood samples collected at ages 7, 9, and 11 years for longitudinal analyses and at age 8 years for cross-sectional analyses.Result(s)In the cross-sectional analysis, AMH levels at age 8 years were lower in pubertal girls (median 25.0 pmol/L, interquartile range [IQR] 16.0–33.9; n = 39) than in prepubertal girls (33.5 pmol/L, IQR 22.3–49.1; n = 342). In prepubertal girls, higher AMH levels were associated with higher inhibin B levels, lower FSH levels, and larger body mass index at age 8 years and subsequently with later age at menarche. AMH levels were unrelated to birth weight or birth length. In the longitudinal analysis, AMH levels increased between ages 7 (median 27.0 pmol/L, IQR 19.2–34) and 9 years (32.0 pmol/L, IQR 26.5–42.7), then declined between 9 and 11 years (26.5 pmol/L, IQR 19–42.25) with high intraindividual correlation in AMH levels between ages 7 and 9 years and 7 and 11 years.Conclusion(s)Measurement of circulating AMH and inhibin B levels suggests that the rate of ovarian primordial follicle recruitment increases in the prepubertal years then declines again following the onset of puberty as follicular activity pattern changes.

Low and Normal IGF-1 Levels in Patients with Chronic Medical Disorders(CMD) is Independent of Anterior Pituitary Hormone Deficiencies: Implications for Treating IGF-1 Abnormal Deficiencies with CMD

Over time, based on evidence-based medicine, a number of hormonal test levels including IGF-1 had been raised or lowered to meet new criteria standards. In particular, IGF-1 plasma levels have been shown in several studies to be an independent diagnostic tool in Adult Growth Hormone Deficiency (AGHD). Many endocrinology studies link low IGF-1 plasma levels with low levels of other anterior pituitary hormones (i.e., LH, FSH, and TSH). Low IGF-1 is considered by most to be between 84-100 µ/l and numerous studies recommend that raising IGF-1 to high normal range reverses Chronic Medical Diseases (CMD), improves bone mineral density (BMD), and fibromyalgia. Moreover, some studies suggest that low levels of IGF-1 by itself independent of anterior pituitary deficiencies is sufficient to determine AGHD in humans. In order to determine the relationship of low IGF-1 with that of LH, FSH, and TSH levels in subjects with CMD, we evaluated these levels (± SD) in 944 patients. Patients with IGF-1 below 84 µ/l, 100 µ/l, and 150 µ/l were accessed. 9.22% had less than 84 µ/l (SD ± 12.52); 19.9% had less than 100 µ/l (SD ± 9.54); and 51.6 had less than 150 µ/l (SD ± 26.0). Specifically, the percentages found for low LH, FSH, and TSH were only 4.2%, 4.8%, and 6.5%. We conclude that IGF-1 deficiencies occur independent of comorbid deficiencies of LH, FSH, and TSH. Finally, we propose that based on the present investigation, IGF-1 low levels between the range of 84-100 µ/l may be too low to be considered as an independent diagnostic marker to treat AGHD with CMD.

Parental Consanguinity in Infertile Males

This study was investigated whether parental consanguinity in males has an effect on or relationship with some infertile subgroups and some semen and hormone parameters. The charts of 2651 infertile males were evaluated retrospectively for parental consanguinity ratios, sperm counts, motility parameters and hormonal values from the records of 2651 infertile males. In 1260 eligible males the first cousin parental consanguinity ratio was 22.6%. In 119 males with nonobstructive azoospermic (NOA) and 430 males with normal sperm counts, the ratios were 34.5% and 20.9%, respectively (p = 0.002). In the NOA group the parental consanguinity ratios were 27.1% (23/85) and 52.9% (18/34) in males with FSH values of >7.6 and 7.6 mIU/ml, respectively (p = 0.007). In males with normal sperm counts if the parents were first cousins, both sperm counts and motility parameters were significantly reduced when compared with the others. To our knowledge, this is the first study of consanguinity ratios among some infertile subgroups. In males with parental consanguinity lower sperm counts and motility ratios in normozoospermic males and lower FSH levels in the NOA group might show a relation with some genetically transmitted defects.

Abstract P2-13-01: Impact of Body Mass Index (BMI) on the efficacy of aromatase inhibitors to suppress estradiol serum levels in postmenopausal patients with early breast cancer: a prospective proof of principle

Abstract Background: BMI impacts on the efficacy of aromatase inhibitors (AIs) regarding disease outcome in patients with early breast cancer. We hypothesized that this clinical impact of BMI is driven by the inability of AIs to suppress estradiol (E2) serum levels to the same low level in obese compared to non-obese patients. Methods: 68 postmenopausal ER positive patients with breast cancer, scheduled to receive anastrozole or letrozole as adjuvant endocrine treatment were prospectively included in this study. Serum was taken before (T1) and 3 months after start with aromatase inhibitors (T2). Serum levels of FSH, LH, E2, glucose and insulin were analyzed immediately in the clinical routine lab and in a dedicated central lab able to measure E2 in serum at low concentrations with high sensitivity. Results: 40 patients were normal - or overweight (non-obese; BMI 18.5–29.9 kg/m2) and 28 patients were obese (BMI ≥ 30 kg/m2). A weak non-significant correlation between BMI and baseline E2 serum levels (r = 0.2, p = 0.2) translated into a strong negative, highly significant correlation between BMI and baseline FSH (r = −0.6, p &amp;lt; 0.01). After 3 months of AI treatment, a moderate correlation between BMI and E2 serum levels (r = 0.35, p = 0.05) and a moderate negative correlation between BMI and FSH (r = −0.34, p = 0.05) could be observed. Aromatase inhibitors significantly suppressed E2 serum levels in non-obese (T1: 18.9 pg/ml, T2: 9.0 pg/ml, p &amp;lt; 0.01) as well as in obese patients (T1: 20.2 pg/ml, T2: 12.5 pg/ml, p &amp;lt; 0.05). In addition an increase in FSH serum levels was observed in obese (T1: 50.0 mIU/ml, T2: 65.5 mIU/ml, p &amp;lt; 0.01) but not in non-obese (T1: 84.0 mIU/ml, T2: 84.6 mIU/ml) patients. However, after 3 months of AI treatment, E2 levels of obese patients were not at the same low level when compared to non-obese patients (E2 obese: 12.5 pg/ml vs. E2 non-obese: 9.0 pg/ml, p = 0.1). This difference translated into significantly lower FSH serum levels in obese compared to non-obese patients (FSH obese: 65.5 mIU/ml vs. FSH: 84.6 mIU/ml, p &amp;lt; 0.01). The significant effects of BMI on FSH serum levels could be detected both in the routine - as well as in the dedicated central lab. Conclusion: AIs are less efficient at suppressing E2 serum levels in obese when compared to non-obese women. The observed effect may contribute to the survival disadvantage of obese patients in adjuvant AI trials. FSH serum levels should be validated as high sensitive surrogate parameters for estradiol serum level suppression by aromatase inhibitors in postmenopausal patients with breast cancer. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-13-01.

Efficacy of different gonadotropin combinations to support ovulation induction in WHO type I anovulation infertility: clinical evidences of human recombinant FSH/human recombinant LH in a 2:1 ratio and highly purified human menopausal gonadotropin stimulation protocols.

The World Helath Organization (WHO) Group I anovulation, or hypogonadotropic hypogonadism (HH), is characterized by reduced hypothalamic/pituitary activity which results in abnormally low serum FSH and LH levels and negligible estrogen activity. To compare the efficacy of human recombinant FSH (r-hFSH) plus human recombinant LH (r-hLH) in a 2:1 ratio with highly purified human menopausal gonadotropin (hMG-HP) urinary extract, containing LH-like activity, in women with HH. This two-arm randomized open-label study included 35 HH women (aged 25-36 yr) attending our Center. Eighteen patients received 150 IU hMG-HP (150 IU FSH + 150 IU LH-like activity) and seventeen received 150IU r-hFSH/75IU rhLH daily for a maximum of 16 days. Ovulation was induced by a single administration of hCG on the day after the last hMG-HP or r-hFSH/r-hLH. The primary efficacy endpoint was ovulation induction as measured by follicle ≥17 mm, pre-ovulatory estradiol (E 2 ) ≥400 pmol/l and mid-luteal phase progesterone (P 4 ) ≥25 nmol/l. Secondary efficacy endpoints included E 2 levels/follicle at mid-cycle, number of follicles at mid-cycle and pregnancy rate (PR). Following a total of 70 cycles, 70% of r-hFSH/r-hLH treated patients met the primary endpoint vs 88% in hMG-HP group (p=0.11). However, PR in r-hFSH/r-hLH group was 55.6% compared to 23.3% in hMG-HP group (p=0.01). The primary endpoint achievement did not correlate with PR. This study has shown the superiority of LH compared to hCG in supporting FSH-induced follicular development in HH women.

MILD ovarian stimulation with GnRH-antagonist vs. long protocol with low dose FSH for non-PCO high responders undergoing IVF: a prospective, randomized study including thawing cycles

To compare the effectiveness of two stimulation protocols in non-polycystic ovary (PCO) high responders undergoing in vitro fertilization (IVF). Prospective randomized trial. A Reproductive Medicine and IVF Unit of a University Hospital and a private IVF Clinic. Four hundred-and-twelve normoovulatory women with good ovarian responsiveness were randomized to receive either the "mild" (FSH 150IU/day from day 4 of a spontaneous cycle followed by GnRH-antagonist from day 8; n = 205) or the "long" (FSH 150IU/day; n = 207) stimulation protocol. The outcome of these two regimens was compared including "fresh" and thawing cycles. The total FSH dose and the peak estradiol level were significantly lower in the "mild" protocol, whereas the retrieved oocytes, fertilization rate, number and quality of embryos, pregnancy and implantation rates, cumulative "fresh plus thaw" success rate, and incidence of severe ovarian hyperstimulation syndrome were comparable with the two regimens. In young, normoovulatory patients with good ovarian responsiveness undergoing IVF the "mild" stimulation protocol has effectiveness and risks comparable to the "long" protocol with low FSH starting dose, even when thawing cycles are included in the comparison.

Polycystic Ovary-Like Abnormalities (PCO-L) in Women with Functional Hypothalamic Amenorrhea

In the general population, about 30% of asymptomatic women have polycystic ovary-like abnormalities (PCO-L), i.e. polycystic ovarian morphology (PCOM) at ultrasound and/or increased anti-Müllerian hormone (AMH) serum level. PCOM has also been reported in 30-50% of women with functional hypothalamic amenorrhea (FHA). The aim of this study was to verify whether both PCOM and excessive AMH level indicate PCO-L in FHA and to elucidate its significance. We conducted a retrospective analysis using a database and comparison with a control population. Subjects received ambulatory care in an academic hospital. Fifty-eight patients with FHA were compared to 217 control women with nonendocrine infertility and body mass index of less than 25 kg/m(2). There were no interventions. We measured serum testosterone, androstenedione, FSH, LH, AMH, and ovarian area values. The antral follicle count (AFC) was used as a binary variable (i.e. negative or positive) because of the evolution of its sensitivity over the time of this study. The ability of these variables (except AFC) to detect PCO-L in both populations was tested by cluster analysis. One cluster (cluster 2) suggesting PCO-L was detected in the control population (n = 52; 24%), whereas two such clusters were observed in the FHA population (n = 22 and n = 6; 38 and 10%; clusters 2 and 3, respectively). Cluster 2 in FHA had similar features of PCO-L as cluster 2 in controls, with higher prevalence of positive AFC (70%) and PCOM (70%), higher values of ovarian area and higher serum AMH (P < 0.0001 for all), and testosterone levels (P < 0.01) than in cluster 1. Cluster 3 in FHA was peculiar, with frankly elevated AMH levels. In the whole population (controls + FHA), PCO-L was significantly associated with lower FSH values (P < 0.0001). PCO-L in FHA is a frequent and usually incidental finding of unclear significance, as in controls. The association of PCO-L with hypothalamic amenorrhea should not lead to a mistaken diagnosis of PCOS.

Influence of hormonal control on LH pulsatility and secretion in women with classical congenital adrenal hyperplasia

Women with classical congenital adrenal hyperplasia (CAH) exhibit reduced fertility due to several factors including anovulation. This has been attributed to a disturbed gonadotropic axis as in polycystic ovary syndrome (PCOS), but there is no precise evaluation. Our aim was to evaluate the gonadotropic axis and LH pulsatility patterns and to determine factor(s) that could account for the potential abnormality of LH pulsatility. Case/control study. Sixteen CAH women (11 with the salt-wasting form and five with the simple virilizing form), aged from 18 to 40 years, and 16 age-matched women, with regular menstrual cycles (28 ± 3 days), were included. LH pulse patterns over 6 h were determined in patients and controls. No differences were observed between patients and controls in terms of mean LH levels, LH pulse amplitude, or LH frequency. In CAH patients, LH pulsatility patterns were heterogeneous, leading us to perform a clustering analysis of LH data, resulting in a two-cluster partition. Patients in cluster 1 had similar LH pulsatility patterns to the controls. Patients in cluster 2 had: lower LH pulse amplitude and frequency and presented menstrual cycle disturbances more frequently; higher 17-OH progesterone, testosterone, progesterone, and androstenedione levels; and lower FSH levels. LH pulsatility may be normal in CAH women well controlled by hormonal treatment. Undertreatment is responsible for hypogonadotropic hypogonadism, with low LH pulse levels and frequency, but not PCOS. Suppression of progesterone and androgen concentrations during the follicular phase of the menstrual cycle should be a major objective in these patients.

Trajectory Clustering of Estradiol and Follicle-Stimulating Hormone during the Menopausal Transition among Women in the Study of Women's Health across the Nation (SWAN)

Variability in the pattern of change in estradiol (E2) and FSH levels over the menopause transition has not been well defined. The current study aimed to determine whether different trajectories of E2 and FSH could be identified and whether race/ethnicity and body mass index were related to the different trajectories. The Study of Women's Health Across the Nation is a longitudinal observational study of the menopausal transition. Women aged 42-52 yr from seven participating sites were recruited and underwent up to 11 annual visits. Postmenopausal women with 12 or more months of amenorrhea that was not due to hysterectomy/oophorectomy and who were not using hormone therapy before the final menstrual period participated in the study. Annual serum E2 and FSH levels anchored to final menstrual period were measured. Four distinct E2 trajectories and three distinct FSH trajectories were identified. The E2 trajectories were: slow decline (26.9%), flat (28.6%), rise/slow decline (13.1%), and rise/steep decline (31.5%). The FSH trajectories were: low (10.6%), medium (48.7%), and high (41.7%) rising patterns. Obesity increased the likelihood of a flat E2 and low FSH trajectory for all race/ethnic groups. Normal-weight Caucasian and African-American women tended to follow the rise/steep decline E2 and high FSH trajectories. Normal-weight Chinese/Japanese women tended to follow the slow decline E2 and the high/medium FSH trajectories. E2 and FSH trajectories over the menopausal transition are not uniform across the population of women. Race/ethnicity and body mass index affect the trajectory of both E2 and FSH change over the menopausal transition.

Male acquired hypogonadotropic hypogonadism: Diagnosis and treatment

Acquired hypogonadotropic hypogonadism (AHH), contrary to congenital hypogonadotropic hypogonadism (CHH) is characterized by postnatal onset of disorders that damage or alter the function of gonadotropin-releasing hormone (GnRH) neurons and/or pituitary gonadotroph cells. AHH thus prevents the establishment of gonadotropin secretion at puberty, or its post-pubertal maintenance. Thus, postnatal AHH may prevent the onset of puberty or appear during pubertal development, but it usually emerges after the normal age of puberty. Although pituitary tumors, particularly prolactinoma, are the most common cause, sellar tumors or cyst of the hypothalamus or infundibulum, infiltrative, vascular, iron overload and other disorders may also cause AHH. Pituitary surgery and head trauma or cranial/pituitary radiation therapy are also usual causes of AHH. The clinical manifestations of AHH depend on age of onset, the degree of gonadotropin deficiency, the rapidity of its onset and the association to other pituitary function deficiencies or excess. Men with AHH have less stamina, decreased libido, erectile dysfunction and strength, and a worsened sense of well being leading to degraded quality of life. The physical examination is usually normal if hypogonadism is of recent onset. Diminished facial, body hair and muscle mass, fine facial wrinkles, gynecomastia, and hypotrophic testes are observed in long-standing and complete AHH. Spermatogenesis is impaired and the volume of ejaculate is decreased only when gonadotropins and testosterone levels are very low. Men with AHH may have normal or low serum LH and FSH concentrations, but normal gonadotropin values are inappropriate when associated with low serum testosterone. In the majority of AHH patients, serum inhibin B is “normal”. The decrease of this sertolian hormone indicates a long-standing and severe gonadotropin deficiency. Symptoms, usually associated with significant testosterone deficiency in men with AHH, improve with testosterone replacement therapy. Replacement therapy is often simple, using an injectable testosterone ester as first line treatment. Fertility can be restored rather quickly, provided there is no independent primary testicular damage and the partner is fertile.

Decreased gonadotropin requirements in once daily compared to twice daily administration: a prospective, randomized study

Despite the lack of any scientific data, many ART programs split the daily gonadotropin dose during ovarian stimulation, while others give the entire dose during a single administration, usually at night. Prospective randomized. 213 women undergoing IVF/ICSI cycles at a single private ART center. Gonadotropin administration once daily compared to twice daily. Gonadotropin usage, clinical and ongoing PR RESULTS: There were 110 women in the once daily compared to 103 in the twice daily arm. All cycles were blastocyst transfers. There was a significantly lower FSH use in the once daily arm compared to the twice daily arm (1507.5 ± 517.5IU vs. 1702.5 ± 622.5, P = 0.015), and a trend towards lower hMG use in the once daily arm (1342.5 ± 562.5IU vs. 1462.5 ± 645.0, P = 0.15), without compromising clinical pregnancy rate (PR) (71.8% vs. 70.9%, P = NS) or delivery/ongoing PR (58.2% vs. 62.1%, P = NS). There were no differences in age, body mass index (BMI), peak estradiol, peak progesterone, retrieved oocytes, fertilized oocytes, number of ET, or PR. Once daily administration is associated with lower gonadotropin usage without compromising success rates.

Solely inhibin B producing ovarian tumour as a cause of secondary amenorrhoea with hot flushes: case report and review of literature

In this report, we describe a case of a solely inhibin B producing fibrothecoma presenting with secondary amenorrhoea and hot flushes. Typical laboratory findings were an elevated LH, elevated inhibin B, low FSH and low estrogen. The World Health Organization classification of amenorrhoea was not applicable since the combination of low estrogen and low FSH suggested a central cause, whereas actually there was an ovarian cause. With staging laparotomy, a bilateral borderline tumour was detected in combination with a fibrothecoma. This report underpins the concept of inhibin B being a selective FSH secretion inhibitor of ovarian origin. Furthermore, a literature review on these topics is included.

Uncovering Novel Reproductive Defects in Neurokinin B Receptor Null Mice: Closing the Gap Between Mice and Men

Patients bearing mutations in TAC3 and TACR3 (which encode neurokinin B and its receptor, respectively) have sexual infantilism and infertility due to GnRH deficiency. In contrast, Tacr3(-/-) mice have previously been reported to be fertile. Because of this apparent phenotypic discordance between mice and men bearing disabling mutations in Tacr3/TACR3, Tacr3 null mice were phenotyped with close attention to pubertal development, estrous cyclicity, and fertility. Tacr3(-/-) mice demonstrated normal timing of preputial separation and day of first estrus, markers of sexual maturation. However, at postnatal d 60, Tacr3(-/-) males had significantly smaller testes and lower FSH levels than their wild-type littermates. Tacr3(-/-) females had lower uterine weights and abnormal estrous cyclicity. Approximately half of Tacr3(-/-) females had no detectable corpora lutea on ovarian histology at postnatal d 60. Despite this apparent ovulatory defect, all Tacr3(-/-) females achieved fertility when mated. However, Tacr3(-/-) females were subfertile, having both reduced numbers of litters and pups per litter. The subfertility of these animals was not due to a primary ovarian defect, because they demonstrated a robust response to exogenous gonadotropins. Thus, although capable of fertility, Tacr3-deficient mice have central reproductive defects. The remarkable ability of acyclic female Tacr3 null mice to achieve fertility is reminiscent of the reversal of hypogonadotropic hypogonadism seen in a high proportion of human patients bearing mutations in TACR3. Tacr3 mice are a useful model to examine the mechanisms by which neurokinin B signaling modulates GnRH release.

Hypogonadism in Men with Sickle Cell Disease (SCD): Benign Hematology Clinic, Detroit Medical Center, Detroit, MI

Abstract 2132Studies have provided conflicting evidence on the etiology of hypogonadism in patients with sickle cell disease. A cross-sectional study was conducted on adult men with SCD to determine whether hypogonadism in these patients is due to primary testicular failure or secondary pituitary / hypothalamic dysfunction and to look for association between hypogonadism and serum ferritin levels. The study protocol was approved by Wayne State University / Detroit Medical Center Human investigation committee.A total of 19 male patients with SCD 18 years or older following at the benign hematology clinic of Detroit Medical Center between Sep 21 to Dec 21; 2011 consented to participate in the study. Blood sample was drawn between 9AM – 11 AM and sent to the laboratory for hormonal assay. A previous pilot study (completed few months earlier) of 15 adult male patients with SCD aged 18years or older at the same site was also included in the analysis. The pilot study was approved by Wayne State University / Detroit Medical Center Human investigation committee. Serum samples from 15 patients with sickle cell disease who had blood work during their routine clinic visit at the benign hematology clinic was assessed for testosterone, FSH and LH levels. Thus a total of 34 male patients with SCD were included in the final analysis. Hormone measurements were done for total testosterone (using immunoassay), FSH and LH using two site sandwich immunoassay by chemilumino method (Siemens, Centaur XP). Additional information on body mass index (BMI), hemoglobin, total bilirubin, ferritin and creatinine levels was collected from the Electronic Medical Record (EMR).Hypogonadism was defined as serum total testosterone level of ≤250 ng/dL. Hypogonadal patients with high FSH and LH were considered as having primary/peripheral hypogonadism where as those with low FSH and LH or inappropriately normal (normal FSH and LH despite low serum testosterone) were considered to have secondary/central hypogonadism. FSH level between 1.5–12.4mIU/ml and LH level of 2–14mIU/ml was considered as normal for male adults. Stata 11.1 was used for statistical analysis. Kruskal-Wallis tests were used to assess the statistical significance of differences in hormone and ferritin levels; no adjustment was made for multiple comparisons.Almost all patients in the study have homozygous SCD-SS genotype except two patients with SCD-SC and one patient with SCD-Sβ+ thalassemia. Additional characteristics of the study population are shown in table 1. Eight of 34 men with SCD (23.6 %) were found to have hypogonadism. Hypogonadal patients were found to have significantly low LH (p=0.006) and FSH (p= 0.01) levels indicating central etiology (Figure 1 and Figure 2). There was no significant difference between hypogonadal and normogonadal with respect to ferritin level (p=0.71) (Figure 3). [Display omitted] [Display omitted] [Display omitted] Our study provides evidence for a central etiology to hypogonadism in male patients with SCD. In this small study ferritin level was not significantly related to hypogonadism. Disclosures:No relevant conflicts of interest to declare.

Toward a pharmacogenetic approach to male infertility: polymorphism of follicle-stimulating hormone beta-subunit promoter

To verify in another population (Italians) whether a single-nucleotide polymorphism in the FSHB gene promoter previously associated with serum FSH levels in Estonians is indeed associated with sperm count and FSH plasma levels, and especially to verify whether it could be a pharmacogenetic tool for the treatment of male infertility with FSH. Cross-sectional and prospective study. Infertility center at a university hospital. Five hundred fourteen subjects with nonobstructive azoospermia and oligozoospermia and 248 subjects with normozoospermia. None. Semen parameters, reproductive hormone levels, and FSHB -211 G/T polymorphism (rs10835638). FSHB -211 TT genotype was associated with significantly lower FSH levels (mean ± SD: 3.3 ± 2.5 IU/L vs. 9.1 ± 8.9 IU/L in GG homozygotes). TT homozygotes were seen in 25% of subjects with azoo-oligozoospermia and low FSH levels (≤1.5 IU/L). We did not observe this genotype in men with high FSH levels (>8 IU/L) or in men with normozoospermia. Treatment with FSH induced a significantly higher improvement in sperm count and quality in TT homozygotes regarding carriers of the G allele. FSHB -211 TT genotype might represent a novel treatable form of male infertility characterized by severe spermatogenic impairment and low or inappropriately normal FSH plasma levels. This genetic marker could represent a valid pharmacogenetic approach for identification of potential responders to FSH treatment.

Contraception by induction of luteinized unruptured follicles with short-acting low molecular weight FSH receptor agonists in female animal models

During recent decades minor innovative drugs have been developed for the female contraceptive market and they all contain steroidal progestagens (and estrogens) that act centrally and have side effects that can be attributed to this central action. In this study, we present an innovative tissue-specific approach for female contraception by low molecular weight (LMW) FSH receptor (FSHR) agonists, which interact with the FSHR that is dominantly expressed in the granulosa cells. The oral administration of LMW FSHR agonists with a short circulation time, induced formation of luteinized unruptured follicles (LUFs) from the Graafian follicles, thereby preventing the release of the oocyte. The short-acting LMW FSHR compounds were fully agonistic to FSHR (EC(50)=4-5 nM). In an isolated mouse follicle culture, a short incubation period (2 h) resulted in inhibition of follicular rupture, where continuous incubation induced follicle growth. Pharmacokinetics after oral administration showed a surge-like exposure in rats and monkeys. Oral administration of short-acting LMW FSHR agonists inhibited ovulation at 10 mg/kg in rats and guinea pigs by generating LUFs without affecting cyclicity. Also, inhibition of follicular rupture was shown to be reversible within one cycle. Finally, LUFs were induced without affecting the hormonal cyclicity in cynomolgus monkeys, a mono-ovulatory species. In healthy women LUF formation occurs naturally, with a LUF acting as corpus luteum that produces enough progesterone to ensure normal menstrual cyclicity. Together with the presented data this indicates that the innovative approach with short-acting LMW FSHR agonists could lead to oral contraception for females at the ovarian level.

Update: Hypogonadotropic Hypogonadism in Type 2 Diabetes and Obesity

Studies over the last few years have clearly established that at least 25% of men with type 2 diabetes have subnormal free testosterone concentrations in association with inappropriately low LH and FSH concentrations. Another 4% have subnormal testosterone concentrations with elevated LH and FSH concentrations. The Endocrine Society, therefore, now recommends the measurement of testosterone in patients with type 2 diabetes on a routine basis. The subnormal testosterone concentrations are not related to glycosylated hemoglobin or duration of diabetes, but are associated with obesity, very high C-reactive protein concentrations, and mild anemia. In addition, subnormal testosterone concentrations in these men are associated with a two to three times elevated risk of cardiovascular events and death in two early studies. Short-term studies of testosterone therapy in hypogonadal men with type 2 diabetes have demonstrated an increase in insulin sensitivity and a decrease in waist circumference. However, the data on the effect of testosterone replacement on glycemic control and cardiovascular risk factors such as cholesterol and C-reactive protein concentrations are inconsistent. As far as sexual function is concerned, testosterone treatment increases libido but does not improve erectile dysfunction and thus, phosphodiesterase inhibitors may be required. Trials of a longer duration are clearly required to definitively establish the benefits and risks of testosterone replacement in patients with type 2 diabetes and low testosterone.