Pulsatile Gonadotropin Releasing Research Articles

Pulsatile gonadotropin releasing hormone therapy for spermatogenesis in congenital hypogonadotropic hypogonadism patients who had poor response to combined gonadotropin therapy.

Both pulsatile gonadotropin-releasing hormone (GnRH) and combined gonadotropin therapy are effective to induce spermatogenesis in men with congenital hypogonadotropic hypogonadism (CHH). This study aimed to evaluate the effect of pulsatile GnRH therapy on spermatogenesis in male patients with CHH who had poor response to combined gonadotropin therapy. Patients who had poor response to combined gonadotropin therapy ≥ 6 months were recruited and shifted to pulsatile GnRH therapy. The rate of successful spermatogenesis, the median time to achieve spermatogenesis, serum gonadotropins, testosterone, and testicular volume were used for data analysis. A total of 28 CHH patients who had poor response to combined gonadotropin (HCG/HMG) therapy for 12.5 (6.0, 17.75) months were recruited and switched to pulsatile GnRH therapy for 10.0 (7.25, 16.0) months. Sperm was detected in 17/28 patients (60.7%). The mean time for the appearance of sperm in semen was 12.0 (7.5, 17.5) months. Compared to those who could not achieve spermatogenesis during pulsatile GnRH therapy, the successful group had a higher level of LH60min (4.32 vs. 1.10 IU/L, P = 0.043) and FSH60min (4.28 vs. 1.90 IU/L, P = 0.021). Testicular size increased during pulsatile GnRH therapy, compared to previous HCG/ HMG therapy (P < 0.05). For CHH patients with prior poor response to one year of HCG/ HMG therapy, switching to pulsatile GnRH therapy may induce spermatogenesis.

Effect of intra-uterine administration of Lactobacillus bacteria on the steroid hormone profile in sub-clinical endometritis affected cows

Infertility in bovines is a major cause of serious economic loss to the dairy farmers. A major reason for infertility is sub-clinical, retrograde uterine infections. Sub-clinical endometritis is endometrial inflammation without apparent clinical manifestation and usually without signs of infection. This condition may be due to uterine infections or an extended inflammatory period that exists after elimination of bacteria. At present, infertility treatment is mainly done with intrauterine antibacterials, antiseptics and less commonly by hormones. These days, the major problem faced by animal reproductive health workers is the multiple drug resistance pathogens because of the indiscriminate use of antibiotics.Therefore, a different approach for more effective treatment of subclinical endometritis with Lactobacilli and its role on the steroid hormone profile was studied. In the present study, estradiol-17 β values were lower in the sub-clinical endometritis affected cows. Whereas, intra-uterine administration of Lactobacillus bacteria caused significant increase in estradiol level in a cycle after treatment in cross- bred cows. Similarly, the circulating serum progesterone concentration was also found to be low in subclinical endometritis affected cows. These findings could be used for clinical and experimental interpretations. Further, the information on pulsatile release of gonadotropins and steroid hormones status, receptors and its control, the close relationship among hormones could be necessary for better understanding of the role of steroid hormones in sub-clinical uterine infections.

FRI275 Glutamate Receptor Agonists Stimulate Kisspeptin Neurons In The Arcuate Nucleus Of The Hypothalamus

Abstract Disclosure: R. Bearss: None. R. Piet: None. KNDy neurons co-express kisspeptin, neurokinin B (NKB), dynorphin A (Dyn A), and glutamate. These neurons, located in the arcuate nucleus of the hypothalamus, drive pulsatile gonadotropin releasing hormone (GnRH) secretion. This eventually promotes pulsatile gonadotropin hormone release from the anterior pituitary, important for fertility in both sexes. The current hypothesized mechanism for pulse generation involves KNDy neuron interconnectivity and reciprocal regulation through the combined actions of NKB, DynA and glutamate to coordinate KNDy neuron activity. There is evidence that KNDy neurons express NKB, Dyn A and glutamate receptors and that NKB stimulates KNDy neuron electrical activity while Dyn A suppresses it. There is also evidence that ionotropic glutamate receptor antagonists can inhibit KNDy neuron coordinated activity and pulsatile gonadotropin hormone release, indicating that glutamatergic neurotransmission plays a significant role in activity coordination. The purpose of the following experiments was to investigate the response of KNDy neurons to varied glutamate receptor activation. We used calcium imaging to monitor the activity of KNDy neurons in brain slices. We crossed Kiss1-Cre mice—expressing Cre recombinase (Cre) in kisspeptin neurons—with Cre-dependent GCaMP6f mice to generate Kiss1-Cre x GCaMP6f mice that express GCaMP6f in kisspeptin neurons. GCaMP6f fluorescence increases when binding to intracellular calcium and can, thus, be used as an inferential marker of electrical activity. Coronal brain slices (200 µm thickness) obtained from male Kiss1-cre x GCaMP6f mice and containing the arcuate nucleus were placed in a recording chamber under an epifluorescence microscope. KNDy neurons were exposed for 2 minutes to a bath application of either the ionotropic glutamate receptor agonist α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA, 10µM), the ionotropic glutamate receptor agonist N-methyl-D-aspartate (NMDA, 50µM), or the group 1 metabotropic glutamate receptor (mGluR) agonist (S)-3,5-dihydroxyphenylglycine (DHPG, 50µM). AMPA, NMDA, and DHPG increased KNDy neuron fluorescence by 7.8±0.5% (n=113 in 7 slices from 6 mice), 7.5±0.5% (n=154 in 6 slices from 5 mice), and 6.1±0.7% (n=159 in 7 slices from 5 mice) respectively. All cells that were excited by NMDA or DHPG were also excited by AMPA. These experiments provide evidence that activation of ionotropic AMPA and NMDA receptors as well as group 1 mGluRs stimulate KNDy neuron activity. Further investigation into the precise role of individual glutamate receptor subtypes on KNDy neuron coordinated activity is needed. Presentation: Friday, June 16, 2023

Macroprolactinemia: a mini-review and update on clinical practice

Hyperprolactinemia is common among infertile patients, with up to 15%-20% of women with oligomenorrhea having hyperprolactinemia. Suppression of the hypothalamic-pituitary-gonadal axis via inhibition of pulsatile gonadotropin releasing hormone because of hyperprolactinemia is a common endocrine etiology of infertility. There are 3 forms of human prolactin (PRL): monomeric PRL, dimeric PRL, and macro-PRL. Also known as big-big PRL, macro-PRL has a molecular weight >150 kDa and normally comprises 5%-10% of circulating PRL. When the predominant form of circulating PRL is macro-PRL, macroprolactinemia is diagnosed. Among patients with hyperprolactinemia, 10%-46% have macroprolactinemia. Patients with macroprolactinemia are at risk of unnecessary pituitary imaging and treatment with dopamine agonists if not correctly diagnosed. Given the high prevalence of macroprolactinemia among patients with elevated PRL levels and the different management of patients with macroprolactinemia vs true monomeric hyperprolactinemia, all patients with persistently elevated PRL levels should be screened for macro-PRL.

Direct evidence that KNDy neurons maintain gonadotropin pulses and folliculogenesis as the GnRH pulse generator.

The gonadotropin-releasing hormone (GnRH) pulse is fundamental for mammalian reproduction: GnRH pulse regimens are needed as therapies for infertile women as continuous GnRH treatment paradoxically inhibits gonadotropin release. Circumstantial evidence suggests that the hypothalamic arcuate KNDy neurons expressing kisspeptin (encoded by Kiss1), neurokinin B (encoded by Tac3), and dynorphin A serve as a GnRH pulse generator; however, no direct evidence is currently available. Here, we show that rescuing >20% KNDy neurons by transfecting Kiss1 inside arcuate Tac3 neurons, but not outside of these neurons, recovered folliculogenesis and luteinizing hormone (LH) pulses, an indicator of GnRH pulses, in female global Kiss1 knockout (KO) rats and that >90% conditional arcuate Kiss1 KO in newly generated Kiss1-floxed rats completely suppressed LH pulses. These results first provide direct evidence that KNDy neurons are the GnRH pulse generator, and at least 20% of KNDy neurons are sufficient to maintain folliculogenesis via generating GnRH/gonadotropin pulses.

HIGH LIVE BIRTH RATES WITH LOW MULTIPLE BIRTH RATES: OVER TWO DECADES' EXPERIENCE OF PULSATILE GNRH PUMP USE FOR OVULATION INDUCTION IN PATIENTS WITH FUNCTIONAL HYPOTHALAMIC AMENORRHEA (FHA)

To analyze the experience of treating patients with FHA (functional hypothalamic amenorrhea) over the last 25 years using a subcutaneous pulsatile gonadotropin releasing hormone (GnRH) pump at a Swiss university-based tertiary referral center.

USE OF THE PULSATILE GnRH PUMP FOR OVULATION INDUCTION IN PATIENTS WITH FUNCTIONAL HYPOTHALAMIC AMENORRHEA (FHA): 5-YEAR EXPERIENCE FROM A SWISS UNIVERSITY HOSPITAL

Congenital or acquired hypogonadotropic hypogonadism (HH) is an important cause of anovulatory infertility. In functional hypothalamic amenorrhea (FHA), loss of function of the hypothalamichypopituitary axis occurs in catabolic states induced by eating disorders, compulsive exercise and high levels of somatic or psychological stress [1]. In patients with FHA attempting to conceive, in addition to addressing the underlying cause, a subcutaneous pulsatile gonadotropin releasing hormone (GnRH) pump may be used to induce ovulation [2].

FSH for the Treatment of Male Infertility.

Follicle-stimulating hormone (FSH) supports spermatogenesis acting via its receptor (FSHR), which activates trophic effects in gonadal Sertoli cells. These pathways are targeted by hormonal drugs used for clinical treatment of infertile men, mainly belonging to sub-groups defined as hypogonadotropic hypogonadism or idiopathic infertility. While, in the first case, fertility may be efficiently restored by specific treatments, such as pulsatile gonadotropin releasing hormone (GnRH) or choriogonadotropin (hCG) alone or in combination with FSH, less is known about the efficacy of FSH in supporting the treatment of male idiopathic infertility. This review focuses on the role of FSH in the clinical approach to male reproduction, addressing the state-of-the-art from the little data available and discussing the pharmacological evidence. New compounds, such as allosteric ligands, dually active, chimeric gonadotropins and immunoglobulins, may represent interesting avenues for future personalized, pharmacological approaches to male infertility.

Inducible Kiss1 knockdown in the hypothalamic arcuate nucleus suppressed pulsatile secretion of luteinizing hormone in male mice.

Accumulating evidence suggests that kisspeptin-GPR54 signaling is indispensable for gonadotropin-releasing hormone (GnRH)/gonadotropin secretion and consequent reproductive functions in mammals. Conventional Kiss1 knockout (KO) mice and rats are reported to be infertile. To date, however, no study has investigated the effect of inducible central Kiss1 KO/knockdown on pulsatile gonadotropin release in male mammals. Here we report an in vivo analysis of inducible conditional Kiss1 knockdown male mice. The mice were generated by a bilateral injections of either adeno-associated virus (AAV) vectors driving Cre recombinase (AAV-Cre) or AAV vectors driving GFP (AAV-GFP, control) into the hypothalamic arcuate nucleus (ARC) of Kiss1-floxed male mice, in which exon 3 of the Kiss1 gene were floxed with loxP sites. Four weeks after the AAV-Cre injection, the mice showed a profound decrease in the both number of ARC Kiss1-expressing cells and the luteinizing hormone (LH) pulse frequency. Interestingly, pulsatile LH secretion was apparent 8 weeks after the AAV-Cre injection despite the suppression of ARC Kiss1 expression. The control Kiss1-floxed mice infected with AAV-GFP showed apparent LH pulses and Kiss1 expression in the ARC at both 4 and 8 weeks after the AAV-GFP injection. These results with an inducible conditional Kiss1 knockdown in the ARC of male mice suggest that ARC kisspeptin neurons are responsible for pulsatile LH secretion in male mice, and indicate the possibility of a compensatory mechanism that restores GnRH/LH pulse generation.

SAT-408 Inducible Kiss1 Knockout in the Hypothalamic Arcuate Nucleus Suppressed Pulsatile LH Secretion in Male Mice

Accumulating evidence suggests that kisspeptin/Gpr54 signaling is indispensable for GnRH/gonadotropin secretion and consequent reproductive functions in mammals. Conventional Kiss1 knockout mice and rats are reported to be infertile. To date, however, no report investigating the effect of inducible central Kiss1 knockout on pulsatile gonadotropin release is available. Here we report in vivo analysis of inducible conditional Kiss1 knockout male mice generated by infection with adeno-associated virus (AAV) vectors driving Cre recombinase (AAV-Cre) in the brain of Kiss1-floxed male mice, in which exon 3 of the Kiss1gene were floxed with LoxP sites. Adult Kiss1-floxed male mice were injected with AAV-Cre or AAV vectors driving GFP (AAV-GFP) bilaterally into the hypothalamic arcuate nucleus (ARC). Four weeks after the AAV-Cre injection, the male mice showed profound decrease in the number of ARC Kiss1-expressing cells and luteinizing hormone (LH) pulse frequency. Interestingly, pulsatile LH secretion was apparent 8 weeks after the AAV-Cre injection despite the suppression of ARC Kiss1 expression. The control Kiss1-floxed animals infected with AAV-GFP showed apparent LH pulses and Kiss1 expression in the ARC both at 4 or 8 weeks after the AAV-GFP injection. These results suggest that ARC Kiss1-expressing cells are responsible for pulsatile LH secretion in male mice and the possibility of compensation mechanism to restore GnRH/LH pulse generation in central Kiss1 knockout mice. This work was supported in part by Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research 18H03973 (to H.T.).

Hyperprolactinaemia in male infertility: Clinical case scenarios

ObjectiveTo explore the evaluation, treatment and impact of hyperprolactinaemia on male infertility and testicular function, as hyperprolactinaemia is commonly detected during the evaluation of infertile men. MethodsA literature search was performed using MEDLINE/PubMed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to identify all studies exploring hyperprolactinaemia in male infertility. ResultsElevated levels of serum prolactin have a detrimental effect on male reproduction through inhibition of the pulsatile release of gonadotrophins from the anterior pituitary gland, and a direct effect on spermatogenesis. Treatment of confirmed hyperprolactinaemia with dopamine agonists leads to significant improvements in both semen parameters and hormone levels. ConclusionHyperprolactinaemia, both directly and indirectly, has a negative effect on sperm production, and its detection and management in men seeking fertility is mandatory.

SB223412, a neurokinin-3 receptor-selective antagonist, suppresses testosterone secretion in male guinea pigs

Guinea pigs are important zoo animals and have been recommended for animal-assisted activities or therapy, however there are problems concerning testosterone inducing aggressive or sexual behaviors in male guinea pigs. Testicular testosterone secretion is regulated by pulsatile gonadotropin releasing hormone (GnRH)/luteinizing hormone (LH) release in mammals. The mechanism generating GnRH/LH pulses is thought to be governed by kisspeptin neurons, which coexpress neurokinin B (NKB) and dynorphin A (Dyn), in the arcuate nucleus (ARC). Kisspeptin neurons in the ARC are frequently referred to as KNDy neurons. The purpose of this study was to examine whether the antagonization of NKB-neurokinin-3 receptor (NK3R) signaling can manipulate testosterone secretion in male guinea pigs. A single subcutaneous administration or 7 days of oral administration of an NK3R-selective antagonist, SB223412 (50 mg/body), significantly decreased plasma testosterone levels in male guinea pigs. In vitro binding assays confirmed that SB223412 has a high affinity to guinea pig NK3R. These results suggest that SB223412 could be used as an orally-available compound to suppress testosterone levels in male guinea pigs. Double labeling in situ hybridization of kisspeptin and either NKB or Dyn showed that kisspeptin-expressing neurons contained NKB (77.9%) or Dyn (62.3%) in the ARC, suggesting the presence of KNDy neurons in the ARC of guinea pigs. In conclusion, the present study shows that SB223412 could be a candidate compound to suppress testosterone secretion in male guinea pigs for controlling sexual and aggressive behaviors in the species.

Case report: An open solution to a persisting problem – Post STARR

To explore the evaluation, treatment and impact of hyperprolactinaemia on male infertility and testicular function, as hyperprolactinaemia is commonly detected during the evaluation of infertile men.A literature search was performed using MEDLINE/PubMed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to identify all studies exploring hyperprolactinaemia in male infertility.Elevated levels of serum prolactin have a detrimental effect on male reproduction through inhibition of the pulsatile release of gonadotrophins from the anterior pituitary gland, and a direct effect on spermatogenesis. Treatment of confirmed hyperprolactinaemia with dopamine agonists leads to significant improvements in both semen parameters and hormone levels.Hyperprolactinaemia, both directly and indirectly, has a negative effect on sperm production, and its detection and management in men seeking fertility is mandatory.

Progress of ovulation induction in female hypogonadotropic hypogonadism

Hypogonadotropic hypogonadism(HH)in women is characterized by failure of ovarian function secondary to deficient gonadotropin secretion, resulting from either a hypothalamic or pituitary defect. Estrogen-progestin therapy can induce and maintain secondary sex characteristic and artificial menstrual cycle. If the patient requires fertility, ovulation and even pregnancy can be induced either with exogenous gonadotropins or with pulsatile gonadotropin releasing hormone therapy. In the present article, different ovulation induction therapies of female HH were reviewed. (Chin J Endocrinol Metab, 2015, 31: 83-85) Key words: Hypogonadotropic hypogonadism; Female; Ovulation induction

Overview and treatment of precocious puberty

Puberty is a complex and coordinated biologic process of sexual development that leads to complete gonadal maturation and function, and attainment of reproductive capacity. The pubertal activation of pulsatile gonadotropinreleasing hormone (GnRH) secretion requires coordinated changes in excitatory ...

Treatment options for females with hypogonadotropic hypogonadism and thromboembolism

Hormon therapy of the female Kallmann’s Syndrome patient in the setting of a pulmonary embolism presents a challenge. A female with hypogonadotropic hypogonadism is usually presented with two treatment options - combined gonadal hormone replacement or pulsatile gonadotropin releasing hormone. When a patient incurs a contraindication to hormonal therapy, the management of their endocrine disorder becomes much more challenging. Providers and patients must consider the advantages and disadvantages to each treatment option, including the possibility of not treating at all. Given the lack of literature on this rare combination of events, herein we review Kallmann’s Syndrome and its therapeutic options, as well as the hypercoagulability associated with hormone therapy to guide our decision-making process in a true case scenario.

What is the optimal therapy for young males with hypogonadotropic hypogonadism?

Hypogonadotropic hypogonadism (HH), consequent to congenital or acquired disorders of the hypothalamic-pituitary axis, presents as absent/delayed/arrested sexual maturation and infertility. Optimal management includes: (a) confirmation of the diagnosis and prognosis, (b) timing and choice of therapeutic intervention and (c) consideration of future fertility prospects. Therapy is usually initiated with testosterone to induce development of secondary sexual characteristics, taking the patient (often diagnosed late) through puberty. Monitoring of the impact of the condition on long-term health and psychosocial function is necessary. Treatment is likely to be life-long, requiring regular monitoring for its optimization and avoidance of adverse responses. Induction of spermatogenesis requires either pulsatile gonadotropin releasing hormone (GnRH) or gonadotropin administration. Gonadotropins can be self-administered subcutaneously and are not inferior to the more costly GnRH. 'Reversible genetic hypogonadotropic hypogonadism' is a recently described entity which has implications for the long-term management of patients with HH.

Endocrine and Local Control of the Primate Corpus Luteum: 1973 to Today.Richard L. Stouffer, Ph.D.

Over 25 years have passed since the annual meeting of the Society for the Study of Reproduction included a session on the comparative aspects and advances in our knowledge of the corpus luteum (CL) in rodent, domestic animal and primate species. Using Dr. E. Knobil's 1973 perspective on the nonhuman and human CL as a starting point, key advances particularly over the past decade will be summarized. In addition, the influence of G. Niswender's research, as related to the elucidation of luteal cell types and the differences between luteinizing hormone (LH) and chorionic gonadotropin (CG)-receptor binding and signaling, will be examined. Finally, recurrent questions and opportunities for further research will be highlighted. Collectively, studies employing pulsatile gonadotropin releasing hormone (GnRH) or GnRH antagonist treatment reinforce the concept that pituitary LH is the primary luteotropic hormone in female monkeys and women, but can we rule out a role for other hormones, including prolactin-like factors? And do local effects of GnRH/GnRH antagonist in the CL complicate our interpretation of the results of LH ablation/replacement protocols? With the advent of monkey and human gene arrays, the transcriptome offers insight into LH-regulated genes (both up- and down-regulated) in the CL, but which are directly regulated by LH versus indirectly via LH-modulated local factors, including steroid hormones and growth factors? Our knowledge of the processes controlling CL development, particularly angiogenesis, has increased, but events leading to CL regression near the end of the nonfertile menstrual cycle remain a mystery. Since the life span of the CL during the menstrual cycle is not regulated by a uterine luteolytic factor, Knobil hypothesized that intraluteal "self-desruct" agents are responsible for luteal regression in primates. Are Knobil's candidates, estradiol and prostaglandin F 2alpha, or other agents, the likely factor(s)? What are the roles of theca-derived and granulosa-derived luteal cells, and luteal cell - nonluteal (microvascular; immune) cell interactions in controlling the functional lifespan of the primate CL? Also, what are the qualities of placental, LH-like CG that rescue the CL and extend its function into early gestation? Opportunities remain for innovative research at the systems, cellular and molecular levels to increase our understanding of primate CL structure-function that is relevant to fertility control and women's health. Supported by NIH NICHD R01HD20869, SCCPIR U54HD18185, CDRC U54HD55744; NCRR P51 RR00163; Schering AG.

Systemic Naloxone Infusion May Trigger Spasticity in Patients With Spinal Cord Injury: Case Series

Background/Objective: Three patients with spinal cord injury (SCI) and 3 able-bodied (AB) patients were infused with naloxone during a study to examine their neuroendocrine function. An unanticipated side effect occurred during the naloxone infusion. All 3 patients with SCI, but none of the AB patients, experienced profoundly increased spasticity during the naloxone infusion. Our report describes this side effect, which has potential implications for the clinical treatment or scientific evaluation of individuals with SCI.Methods: All patients were in good general health and medication free for 11 days or longer before the study. Each patient was placed on a 30-hour protocol to analyze pulsatile release of gonadotropins. Physiologic saline was intravenously infused on day 1 to serve as a control period for naloxone infusion on day 2.Results: AB patients experienced no muscle spasm activity or any other side effects at any time during the study. In contrast, all 3 patients with SCI experienced a profoundly increased frequency and duration of spasticity in muscles innervated by the nerve roots caudal to their level of injury. In all 3 patients with SCI, spasticity increased only during the period of naloxone infusion. Within 1 hour of stopping naloxone, spasticity returned to baseline levels.Conclusions: Naloxone infusion produced a differential effect on the muscle activity of men with SCI compared to AB men with intact spinal circuits. Consistent with previous studies, the results of this study indicate a relationship between opioid neuromodulation and spasticity after SCI.

Estrogenic ovulatory dysfunction or functional female hyperandrogenism: an argument to discard the term polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders seen among reproductive-age women, with a prevalence of 4%-9% depending on the criteria used to define the syndrome. The diagnostic criteria for PCOS have been surprisingly controversial and confusing for patients, clinicians, and researchers. We believe that the confusion surrounding PCOS arises almost entirely because its name refers to a trait that is inconsistently present and irrelevant to both the etiology and the treatment of the disorder. We suggest that merely abandoning the term PCOS will cure much of what has ailed us for decades and allow us to focus on the etiology and treatment of the causes of what the experts in this field have come to recognize as functional female hyperandrogenism.