High-dose Follicle-stimulating Hormone Research Articles

Consecutive ovarian stimulation is beneficial in patients with a poor response to high-dose follicle-stimulating hormone

Objective To investigate if an immediate additional IVF-ET cycle bear an advantage to patients with poor ovarian response in comparison to a cycle performed at some delay. Methods A cohort study including 632 patients who underwent a fresh IVF-ET cycle with high-dose (≥300 IU/d) FSH stimulation that yielded ≤4 oocytes and did not achieve a clinical pregnancy. All underwent a second stimulation and oocyte pick-up (OPU), either consecutively or separately within 180 days (nonconsecutive OPU). The oocyte yield, number of embryos available for transfer, pregnancy live birth rates of the second OPU were compared between patients who had consecutive and nonconsecutive cycles. Results Consecutive OPU was associated with more mature follicles in the second cycle compared to nonconsecutive OPU (p = .03) in addition to higher peak estradiol level (p < .0001), and more aspirated oocytes (p = .03) and available embryos (p = .023). There was no between-group difference in ongoing pregnancy and live birth rates. In a multivariate analysis of variance controlling for potential confounders, the difference in the number of aspirated oocytes and available embryos was associated significantly only with consecutive performance of the second cycle. Conclusion Immediate sequential stimulation (without an intervening menstrual cycle) in poor responders is advantageous over delayed stimulation in terms of number of aspirated oocytes and available embryos. The administration of high-dose FSH in the first cycle may benefit follicular recruitment also in the subsequent cycle. Although the effect is modest, given that each additional oocyte aspirated contributes to the outcome, it might be of significance especially in younger patients.

Role of Follicle-Stimulating Hormone in Spermatogenesis.

Spermatogenesis is a concerted sequence of events during maturation of spermatogonia into spermatozoa. The process involves differential gene-expression and cell-cell interplay regulated by the key endocrine stimuli, i.e., follicle-stimulating hormone (FSH) and luteinizing hormone (LH)-stimulated testosterone. FSH affects independently and in concert with testosterone, the proliferation, maturation and function of the supporting Sertoli cells that produce regulatory signals and nutrients for the maintenance of developing germ cells. Rodents are able to complete spermatogenesis without FSH stimulus, but its deficiency significantly decreases sperm quantity. Men carrying loss-of-function mutation in the gene encoding the ligand (FSHB) or its receptor (FSHR) present, respectively, with azoospermia or suppressed spermatogenesis. Recently, the importance of high intratesticular testosterone concentration for spermatogenesis has been questioned. It was established that it can be completed at minimal intratesticular concentration of the hormone. Furthermore, we recently demonstrated that very robust constitutive FSHR action can rescue spermatogenesis and fertility of mice even when the testosterone stimulus is completely blocked. The clinical relevance of these findings concerns a new strategy of high-dose FSH in treatment of spermatogenic failure.

Constitutively active follicle-stimulating hormone receptor enables androgen-independent spermatogenesis.

Spermatogenesis is regulated by the 2 pituitary gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). This process is considered impossible without the absolute requirement of LH-stimulated testicular testosterone (T) production. The role of FSH remains unclear because men and mice with inactivating FSH receptor (FSHR) mutations are fertile. We revisited the role of FSH in spermatogenesis using transgenic mice expressing a constitutively strongly active FSHR mutant in a LH receptor–null (LHR-null) background. The mutant FSHR reversed the azoospermia and partially restored fertility of Lhr–/– mice. The finding was initially ascribed to the residual Leydig cell T production. However, when T action was completely blocked with the potent antiandrogen flutamide, spermatogenesis persisted. Hence, completely T-independent spermatogenesis is possible through strong FSHR activation, and the dogma of T being a sine qua non for spermatogenesis may need modification. The mechanism for the finding appeared to be that FSHR activation maintained the expression of Sertoli cell genes considered androgen dependent. The translational message of our findings is the possibility of developing a new strategy of high-dose FSH treatment for spermatogenic failure. Our findings also provide an explanation of molecular pathogenesis for Pasqualini syndrome (fertile eunuchs; LH/T deficiency with persistent spermatogenesis) and explain how the hormonal regulation of spermatogenesis has shifted from FSH to T dominance during evolution.

Follicle-stimulating hormone enhances hepatic gluconeogenesis by GRK2-mediated AMPK hyperphosphorylation at Ser485 in mice.

Increased serum follicle-stimulating hormone (FSH) is correlated with fasting hyperglycaemia. However, the underlying mechanism remains unclear. Because excessive hepatic gluconeogenesis is a major cause of fasting hyperglycaemia the present study investigated whether FSH increases hepatic gluconeogenesis in mice. Ovariectomised mice supplemented with oestradiol (E2) to maintain normal levels of serum E2 (OVX+E2 mice) were injected with low or high doses of FSH. We knocked out Crtc2, a crucial factor in gluconeogenesis, and Fshr to discern their involvement in FSH signalling. To evaluate the role of the G-protein-coupled receptor (GPCR) kinase 2 (GRK2), which could affect glucose metabolism and interact directly with non-GPCR components, a specific GRK2 inhibitor was used. The pyruvate tolerance test (PTT), quantification of PEPCK and glucose-6-phosphatase (G6Pase), key enzymes of gluconeogenesis, GRK2 and phosphorylation of AMP-activated protein kinase (AMPK) were examined to evaluate the level of gluconeogenesis in the liver. A nonphosphorylatable mutant of AMPK Ser485 (AMPK S485A) was transfected into HepG2 cells to evaluate the role of AMPK Ser485 phosphorylation. FSH increased fasting glucose (OVX+E2+high-dose FSH 8.18 ± 0.60mmol/l vs OVX+E2 6.23 ± 1.33mmol/l), the PTT results, and the transcription of Pepck (also known as Pck1; 2.0-fold increase) and G6pase (also known as G6pc; 2.5-fold increase) in OVX+E2 mice. FSH also enhanced the promoter luciferase activities of the two enzymes in HepG2 cells. FSH promoted the membrane translocation of GRK2, which is associated with increased AMPK Ser485 and decreased AMPK Thr172 phosphorylation, and enhanced the nuclear translocation of cyclic AMP-regulated transcriptional coactivator 2 (CRTC2). GRK2 could bind with AMPK and induce Ser485 hyperphosphorylation. Furthermore, either the GRK2 inhibitor or AMPK S485A blocked FSH-regulated AMPK Thr172 dephosphorylation and gluconeogenesis. Additionally, the deletion of Crtc2 or Fshr abolished the function of FSH in OVX+E2 mice. The results indicate that FSH enhances CRTC2-mediated gluconeogenesis dependent on AMPK Ser485 phosphorylation via GRK2 in the liver, suggesting an essential role of FSH in the pathogenesis of fasting hyperglycaemia.

Diminished ovarian reserve and premature ovarian failure: A review

Diminished ovarian reserve (DOR) is defined as reduced capacity of the ovaries to produce oocytes; the oocytes produced are of poorer quality leading to the formation of poor quality embryos. The most severe form of DOR can be represented as premature ovarian failure (POF). There are various reasons leading to DOR, the most important factor being increasing age, others being endometriosis and surgeries on the ovary. POF can be due to chromosomal aberrations or secondary to chemotherapy, radiotherapy, infections, or surgeries involving the ovaries. Patients with DOR may present with infertility and menstrual cycle abnormalities; patients with sudden onset POF may also present with hot flushes and vaginal dryness. There are various tests for finding out ones's ovarian reserve, the most widely used being follicle-stimulating hormone (FSH), anti-Mullerian hormone, and antral follicle count. It is important to know a patient's ovarian reserve before recruiting her for in vitro fertilization. Various modalities have been tried to improve the outcome in candidates with DOR undergoing assisted reproductive technology. This includes high-dose FSH treatment, luteinizing hormone supplementation, GnRH antagonist cycle, and use of adjuvant treatments such as estrogen priming, growth hormone, L-arginine, and dehydroepiandrosterone. Patients who are planned for chemotherapy or radiotherapy may undergo oocyte or embryo cryopreservation before the cancer treatment. To conclude, patients with DOR and POF should be provided with good counseling and emotional support.

Controlled ovarian hyperstimulation for low responders in in vitro fertilization/intracytoplasmic sperm injection: a low-dose flare protocol

In this retrospective study of 652 anticipated low response women, the overall clinical outcomes (live birth rate and clinical pregnancy rate [PR]) of low-dose flare (LDF) protocol appeared lower than those of conventional down-regulation (DR) (LDF: 15.1% vs. DR: 20.6% and LDF: 10.3% vs. DR: 17.4%, respectively). The findings that LDF protocol improved the clinical outcome in older women, or when LDF followed an unsuccessful IVF/intracytoplasmic sperm injection (ICSI) cycle with DR (LDF: 19.4% vs. DR: 9.76% and LDF: 13.9% vs. DR: 4.2% respectively), need further evaluation through randomized trials.

Early follicular rise of serum progesterone concentration in response to a flare-up effect of gonadotrophin-releasing hormone agonist impairs follicular recruitment for in-vitro fertilization

A retrospective study of 150 cycles of in-vitro fertilization (IVF) was undertaken to determine the impact of elevated serum progesterone in the early follicular phase of IVF cycles utilizing gonadotrophin-releasing hormone agonist (GnRHa) initiated in the follicular phase. A total of 127 patients identified as being at risk for poor response to stimulation were treated with a flare-up protocol of GnRHa combined with high dose follicle stimulating hormone (FSH). Patients were excluded for severe male factor requiring micromanipulation. Patients were stimulated with GnRHa beginning on cycle day 2, and high dose FSH beginning on cycle day 3. Some 85% of the cycles exhibited a rise of serum progesterone to a peak concentration of > 1.0 ng/ml (range, 1.2-4.2 ng/ml) during cycle days 2-6. When compared to cycles with no demonstrable progesterone rise, cycles with a rise were associated with a significantly decreased ovarian response: more ampoules of gonadotrophin were required (mean 26.8 versus 22.6, P < 0.05), lower peak oestradiol concentration was reached (mean 774 pg/ml versus 1030; P < 0.05), and fewer mature oocytes were harvested (mean 4.6 versus 7.5; P < 0.01). Among the different pregnancy outcomes (clinical pregnancy, no pregnancy, ongoing pregnancy, and miscarriage), there were no significant differences detected in the early follicular progesterone concentrations as measured by peak progesterone, progesterone area under the curve (days 2-6), and day of peak progesterone. The follicular phase initiation of GnRHa can result in significant elevations of serum progesterone in the early follicular phase, which may impair follicular recruitment and overall ovarian response.

High-dose follicle-stimulating hormone stimulation at the onset of the menstrual cycle does not improve the in vitro fertilization outcome in low-responder patients

In an attempt to improve their outcome with in vitro fertilization (IVF), 34 low-responder patients were stimulated with six ampules of follicle-stimulating hormone (FSH) daily starting on day 1 (n = 17) or day 2 (n = 17) of their menstrual cycles. The stimulated cycles showed a mean peak estradiol of 443 +/- 173 pg/mL, mean days of human chorionic gonadotropin of 7.6 +/- 1.4, 2.67 +/- 1.5 preovulatory oocytes per retrieval, and 2.56 +/- 1.3 oocytes per transfer. Three clinical pregnancies resulted after 25 embryo transfer cycles (12%). With paired analysis, we compared 8 patient cycles with prior six ampules of FSH stimulation starting on day 3; all parameters examined showed no significant differences. In a comparison of 22 patient cycles with prior 4 ampules of FSH stimulation on cycle day 3, no significant differences in any parameters were observed except in the higher number of ampules used in the present study. We conclude that high-dose FSH stimulation at the onset of the menstrual cycle does not improve the IVF outcome in low-responder patients.

High-dose follicle-stimulating hormone stimulation at the onset of the menstrual cycle does not improve the in vitro fertilization outcome in low-responder patients

In an attempt to improve their outcome with in vitro fertilization (IVF), 34 low-responder patients were stimulated with six ampules of follicle-stimulating hormone (FSH) daily starting on day 1 (n = 17) or day 2 (n = 17) of their menstrual cycles. The stimulated cycles showed a mean peak estradiol of 443 ± 173 pg/mL, mean days of human chorionic gonadotropin of 7.6 ± 1.4, 2.67 ± 1.5 preovulatory oocytes per retrieval, and 2.56 ± 1.3 oocytes per transfer. Three clinical pregnancies resulted after 25 embryo transfer cycles (12%). With paired analysis, we compared 8 patient cycles with prior six ampules of FSH stimulation starting on day 3; all parameters examined showed no significant differences. In a comparison of 22 patient cycles with prior 4 ampules of FSH stimulation on cycle day 3, no significant differences in any parameters were observed except in the higher number of ampules used in the present study. We conclude that high-dose FSH stimulation at the onset of the menstrual cycle does not improve the IVF outcome in low-responder patients.

High-dose follicle-stimulating hormone (FSH) ovarian stimulation in low-responder patients for in vitro fertilization

Follicle-stimulating hormone (FSH) was used in high doses (6 ampoules/day:6FSH) for ovarian hyperstimulation for in vitro fertilization in women with a previous poor response to stimulation with the equivalent of "4FSH." Luteinizing hormone levels did not differ between stimulations, but both FSH and estradiol levels were higher in the 6FSH compared to the 4FSH cycle. There were fewer cancellations in the 6FSH cycle, but similar numbers of preovulatory oocytes were retrieved, fertilized, and transferred. The pregnancy rates per attempt and retrieval were higher in the 6FSH cycle. We conclude that raising and maintaining FSH levels during stimulation in low responders reduced cancellations and may improve in vitro fertilization outcome.