Context:17β-Estradiol (E2) is increasingly administered subcutaneously (SC) to transgender women, but questions remain regarding dosing and efficacy. Objectives:The primary aims of this work were to determine if SC E2 could consistently achieve serum E2 and total testosterone (TT) levels within target therapeutic ranges and if TT and E2 levels were comparable to those achieved with standard oral therapy. The secondary aim was to determine if serum estrone (E1) and sex hormone-binding globulin (SHBG) levels were lower with SC compared to oral administration, possibly reflecting fewer first-pass hepatic effects. Methods:This retrospective cohort study evaluated records of transgender women receiving either SC or oral E2 in the Reproductive Endocrinology and Gender Clinics at Maine Medical Center. Serum levels of E2, TT, E1, and SHBG were extracted from charts. Results:Demographics were similar in SC (n = 25) and oral (n = 20) groups. Serum E2 reached the target therapeutic range (75-250 pg/mL) and TT was suppressed to less than 50 ng/mL in all patients and were not statistically different between groups. In 5 patients in the SC group, E2 was measured before and after dosing, with mean values within the target range. The median (interquartile range) E1 level was higher in the oral E2 group than in the SC E2 group (907 pg/mL [737-1576 pg/mL] and 76 pg/mL [49-96 pg/mL]; P < .001). SHBG levels did not differ between groups. Conclusion:SC E2 administration is effective in transgender women for achieving target serum E2 and TT levels. Both SC and orally administered E2 achieved similar E2 and TT levels, but orally administered E2 resulted in much higher E1 levels.

Abstract Disclosure: H. Perkins: None. H. Moreau: None. J. LaBudde: None. W. Craig: None. D.I. Spratt: None. Background: Off-label use of subcutaneous (SC) estradiol (E2) by transgender women for gender-affirming hormone therapy is becoming increasingly widespread, despite a lack of published data regarding its efficacy and safety. Methods: This retrospective cohort study used manual data extraction from electronic medical records for patients ages 18-79 years, currently or previously receiving oral (PO) 17-beta E2 or SC E2 valerate therapy at Maine Medical Center Reproductive Endocrinology and Infertility and Gender Clinics between 5/30/14-5/30/23, who completed E2 dose adjustments aimed at obtaining a serum E2 of 75-250 pg/mL. SC E2 was administered weekly and PO E2 daily. Serum testosterone (T), estrone (E1), and sex hormone binding globulin (SHBG) levels were recorded if drawn within 90 days of E2 measurement on an optimized dose. In a subset of patients receiving SC E2, serum E2 levels were drawn 1-2 days post- and pre-injection. All patient-reported local or systemic reactions were recorded. Data are expressed as median (full range) or mean ± standard deviation (full range). Results: 45 patients were included with no significant differences in demographics between PO (n=20) and SC (n=25) groups. Both groups achieved therapeutic E2 levels after dose adjustment without statistical difference in mean serum E2 (pg/mL) between SC and PO groups: 148.7 ± 41.0 (78-226) vs. 151.6 ± 31.7 (97-208); p=0.79 by t-test. In patients without orchiectomy, both SC and PO groups had T (ng/dL) suppressed to normal adult female range (10-55) in 11/12 SC patients and in 17/17 PO patients; median T was 14.0 (7.7-86) for SC vs. 20.6 (3.4-42) for PO; p=0.98 by Mann-Whitney U test. Median E2 dose (mg/week) in the SC group was 3.0 (1.4-6.0) and in the PO group was 42.0 (28-84). Median serum E1 (pg/mL) was lower in the SC group than the PO group: 73.5 (29-115), n=12 vs. 907 (596-1601), n=5, p<0.001 by Mann-Whitney U test. E1/E2 ratio was lower in the SC group than the PO group: 0.4 ± 0.1 vs. 8.0 ± 2.9; p<0.001 by t-test. There was no significant difference in median serum SHBG (nmol/L) between SC and PO groups: 71.7 (19.3-146.7), n=15 vs. 73.4 (51.0-187.4), n=14; p=0.20 by Mann-Whitney U test. Mean post- and pre-dose serum E2 levels in 5 patients were 138.0 ± 24.0 and 88.0 ± 57.6, respectively. There was one transient local reaction and no systemic allergic or inflammatory reactions in the SC group with no systemic reactions in the PO group. Conclusion: These results demonstrate that SC E2 at doses of 1.4-6 mg/week can be administered safely to achieve therapeutic serum E2 levels and suppress serum T levels to within the normal female range. Our preliminary data reveal lower serum E1 levels in the SC group than in the PO group suggesting reduced hepatic first-pass metabolism with SC administration; this pattern was not seen with serum SHBG levels. Post- and pre-dose serum E2 levels revealed only a mild decline in E2 levels between injections. Presentation: 6/3/2024

Abstract Disclosure: H. Perkins: None. H. Moreau: None. J. LaBudde: None. W. Craig: None. D.I. Spratt: None. Background: Off-label use of subcutaneous (SC) estradiol (E2) by transgender women for gender-affirming hormone therapy is becoming increasingly widespread, despite a lack of published data regarding its efficacy and safety. Methods: This retrospective cohort study used manual data extraction from electronic medical records for patients ages 18-79 years, currently or previously receiving oral (PO) 17-beta E2 or SC E2 valerate therapy at Maine Medical Center Reproductive Endocrinology and Infertility and Gender Clinics between 5/30/14-5/30/23, who completed E2 dose adjustments aimed at obtaining a serum E2 of 75-250 pg/mL. SC E2 was administered weekly and PO E2 daily. Serum testosterone (T), estrone (E1), and sex hormone binding globulin (SHBG) levels were recorded if drawn within 90 days of E2 measurement on an optimized dose. In a subset of patients receiving SC E2, serum E2 levels were drawn 1-2 days post- and pre-injection. All patient-reported local or systemic reactions were recorded. Data are expressed as median (full range) or mean ± standard deviation (full range). Results: 45 patients were included with no significant differences in demographics between PO (n=20) and SC (n=25) groups. Both groups achieved therapeutic E2 levels after dose adjustment without statistical difference in mean serum E2 (pg/mL) between SC and PO groups: 148.7 ± 41.0 (78-226) vs. 151.6 ± 31.7 (97-208); p=0.79 by t-test. In patients without orchiectomy, both SC and PO groups had T (ng/dL) suppressed to normal adult female range (10-55) in 11/12 SC patients and in 17/17 PO patients; median T was 14.0 (7.7-86) for SC vs. 20.6 (3.4-42) for PO; p=0.98 by Mann-Whitney U test. Median E2 dose (mg/week) in the SC group was 3.0 (1.4-6.0) and in the PO group was 42.0 (28-84). Median serum E1 (pg/mL) was lower in the SC group than the PO group: 73.5 (29-115), n=12 vs. 907 (596-1601), n=5, p<0.001 by Mann-Whitney U test. E1/E2 ratio was lower in the SC group than the PO group: 0.4 ± 0.1 vs. 8.0 ± 2.9; p<0.001 by t-test. There was no significant difference in median serum SHBG (nmol/L) between SC and PO groups: 71.7 (19.3-146.7), n=15 vs. 73.4 (51.0-187.4), n=14; p=0.20 by Mann-Whitney U test. Mean post- and pre-dose serum E2 levels in 5 patients were 138.0 ± 24.0 and 88.0 ± 57.6, respectively. There was one transient local reaction and no systemic allergic or inflammatory reactions in the SC group with no systemic reactions in the PO group. Conclusion: These results demonstrate that SC E2 at doses of 1.4-6 mg/week can be administered safely to achieve therapeutic serum E2 levels and suppress serum T levels to within the normal female range. Our preliminary data reveal lower serum E1 levels in the SC group than in the PO group suggesting reduced hepatic first-pass metabolism with SC administration; this pattern was not seen with serum SHBG levels. Post- and pre-dose serum E2 levels revealed only a mild decline in E2 levels between injections. Presentation: 6/3/2024

The primary aim of this study was to determine if SC injection of E2 valerate could produce serum E2 levels within our clinic’s target therapeutic range for MTF patients (75-200 pg/mL) without causing significant adverse effects. Secondary aims were to assess: 1) if SC E2 can suppress serum total testosterone (T) levels (<50 ng/dL) as effectively as oral (PO) E2 , 2) if SC administration has less of a hepatic effect than PO, 3) if serum E2 levels remain within the target range between weekly injections and 4) if SC E2 is acceptable to patients. Retrospective chart review of MTF patients treated in Maine Medical Center Reproductive Endocrinology clinic. All charts of MTF patients seen from 2011-2020 were reviewed. Patients were allowed to choose PO, SC or transdermal (TD) administration. Inclusion criteria were age 18-79 years, PO or SC E2 therapy, and serum E2 and T levels measured by LabCorp (Calabasas CA). E2 valerate was injected SC using a 5/8’ 25g needle. 17β-E2 was administered orally. Serum E2, T, estrone (E1), and sex hormone binding globulin (SHBG) levels and fasting lipid panels were measured in SC and PO patients and values compared by Mann Whitney U test. Peak and nadir serum E2 concentrations were measured in a subgroup of SC patients. Serum sex steroid concentrations were measured by liquid chromatography/mass spectrometry. Local and systemic adverse effects were assessed by history and physical exam. The study was approved by the Maine Medical Center IRB. 102 charts were reviewed. Of 65 patients who were offered PO, TD or SC therapy (the SC option became available in May 2017), 23 choose SC. 61 patients were included in the final analysis, 23 in the SC group and 38 in the PO group. Median dose of E2 for the PO group was 4 mg/day [full range=1-12]; for SC E2 it was 4 mg/week [full range=2-6]. For the SC and PO groups the median E2 were 155.5 [75-291] (n=18) and 122 [76-208] pg/mL (n=38) respectively. Median and range of serum T levels in the SC and PO groups were 16 [4.5-82] (n=14) and 13 [4.8-515] (n=38) ng/dL respectively. E1 serum levels in the SC and PO groups were 49.0 [31.0-104.0] (n=10) and 495 [198-926] (n=12) pg/mL (p=0.003). SHBG and lipid levels did not vary significantly between the two groups (not shown). In a subgroup of SC patients, the median serum E2 decreased from 212 [158-245] to 112 [87-150] pg/mL from the day after to the day before an injection (n=12). 22/23 patients in the SC group chose to continue this method, 0/23 patients experienced a systemic reaction and 1/23 experienced a local site reaction. These preliminary data suggest that SC E2 injection is a safe and effective option for administration of E2 that appears to be well accepted by patients. It is well absorbed with minimal adverse effects and suppresses serum T levels as effectively as PO E2. SC E2 has less hepatic effect as reflected by serum E1 levels (but not SHBG or lipids in this small sample size). Serum E2 levels decrease between weekly injections and additional studies are required to refine dosing to maintain E2 values within the target range. Additional pharmacodynamic studies are also indicated.

Context: The increase in circulating estrogen levels with acute illness in humans is accompanied by increased aromatase expression in adipose tissue and increased peripheral aromatization of estrogens to androgens. Animal studies indicate that estrogen may be beneficial in acute illness. Objective: We hypothesized that blockade of aromatase in acute illness would decrease survival. Design: Prospective sham controlled. Setting: Maine Medical Center Research Institute animal facility. Animals: Six- to 8-week-old male black 6 mice. Intervention: Mice underwent cecal ligation and puncture (CLP) to induce acute illness and were administered letrozole to block aromatase or saline. Mice undergoing sham surgery with or without letrozole served as controls. Adipose and cardiovascular tissue was harvested for preliminary evaluation of aromatase expression. Main outcome measurements: Survival was the main outcome measurement. Evidence for aromatase expression in tissue samples was assessed using western blot and/or immunohistochemistry. Results: With aromatase blockade, survival in CLP mice was decreased (P = 0.04). The presence of aromatase in adipose tissue was observed by western blot in CLP but not control mice. Similarly, the presence of aromatase was observed in cardiac tissue of CLP but not in control mice. Conclusions: The decreased survival during sepsis with aromatase blockade suggests that this response to acute illness may be important both physiologically and clinically. The preliminary observation of aromatase expression in adipose and cardiovascular tissue during acute illness in this mouse model indicates that this model has parallels to human physiology and may be useful for further studying the aromatase response to acute illness.

Context Testosterone (T) is commonly administered intramuscularly to treat hypogonadal males and female-to-male (FTM) transgender patients. However, these injections can involve significant discomfort and may require arrangements for administration by others. Objective We assessed whether T could be administered effectively and safely subcutaneously as an alternative to intramuscular (IM) injections. Design Retrospective cohort study. Setting Outpatient reproductive endocrinology clinic at an academic medical center. Patients Sixty-three FTM transgender patients aged >18 years electing to receive subcutaneous (SC) T therapy for sex transition were included. Fifty-three patients were premenopausal. Intervention Patients were administered T cypionate or enanthate weekly at an initial dose of 50 mg. Dose was adjusted if needed to achieve serum total T levels within the normal male range. Main Outcome Measurements Serum concentrations of free and total T and total estradiol (E2), masculinization, and surveillance for reactions at injection sites. Results Serum T levels within the normal male range were achieved in all 63 patients with doses of 50 to 150 mg (median, 75/80 mg). Therapy was effective across a wide range of body mass index (19.0 to 49.9 kg/m2). Minor and transient local reactions were reported in 9 out of 63 patients. Among 53 premenopausal patients, 51 achieved amenorrhea and 35 achieved serum E2 concentrations <50 pg/mL. Twenty-two patients were originally receiving IM and switched to SC therapy. All 22 had a mild (n = 2) or marked (n = 20) preference for SC injections; none preferred IM injections. Conclusions Our observations indicate that SC T injections are an effective, safe, and well-accepted alternative to IM T injections.

PURPOSE:Intramuscular (IM) testosterone is the most common modality for testosterone therapy of both male hypogonadism and female-to-male (FTM) gender transition. However, IM injections can be painful and often are not self-administered by the patient. The objective of this study was to further characterize subcutaneous (SC) administration of testosterone as an effective and safe alternative to IM injections by evaluating the pharmacodynamics of serum total and free testosterone concentrations between weekly testosterone injections.METHODS:Eleven FTM transgender patients already receiving weekly SC testosterone cypionate with documented therapeutic levels prior to enrollment had free and total serum testosterone levels measured at eight different time points during a 1-week dosing interval.RESULTS:Mean levels of total and free testosterone were stable and remained well within the normal range between injections. Overall mean ± standard deviation levels for the seven samples taken between injections were 627 ± 206 ng/dL (range, 205 to 1410) for total testosterone and 146 ± 51 pg/mL (range, 38 to 348) for free testosterone. No adverse effects were encountered.CONCLUSIONS:The results of this study support use of SC testosterone to achieve therapeutic and stable serum testosterone levels for the purpose of gender transition. It is anticipated that these results can be extended to hypogonadal men. This route may be preferred over IM testosterone because it is relatively painless and easy to self-inject thus allowing for the convenience and economy of patient self-administration.

SummaryA 55-year-old woman with asthma presented with adrenal insufficiency of unknown origin. She was referred to our Division of Reproductive Endocrinology to further evaluate an undetectable morning cortisol level discovered during the evaluation of a low serum DHEA-S level. She was asymptomatic other than having mild fatigue and weight gain. Her medication list included 220 μg of inhaled fluticasone propionate twice daily for asthma, which she was taking as prescribed. On presentation, the undetectable morning cortisol level was confirmed. A urinary measurement of fluticasone propionate 17β-carboxylic acid was markedly elevated. Fluticasone therapy was discontinued and salmeterol therapy initiated with supplemental hydrocortisone. Hydrocortisone therapy was discontinued after 2 months. A repeat urinary fluticasone measurement 4 months after the discontinuation of fluticasone therapy was undetectably low and morning cortisol level was normal at 18.0 μg/dl. Inhaled fluticasone is generally considered to be minimally systemically absorbed. This patient's only clinical evidence suggesting adrenal insufficiency was fatigue accompanying a low serum DHEA-S level. This case demonstrates that adrenal insufficiency can be caused by a routine dose of inhaled fluticasone. Missing this diagnosis could potentially result in adrenal crisis upon discontinuation of fluticasone therapy.Learning pointsStandard-dose inhaled fluticasone can cause adrenal insufficiency.Adrenal insufficiency should be considered in patients taking, or who have recently discontinued, inhaled fluticasone therapy and present with new onset of nonspecific symptoms such as fatigue, weakness, depression, myalgia, arthralgia, unexplained weight loss, and nausea that are suggestive of adrenal insufficiency.Adrenal insufficiency should be considered in postoperative patients who exhibit signs of hypoadrenalism after fluticasone therapy has been withheld in the perioperative setting.Routine screening for hypoadrenalism in patients without clinical signs or symptoms of adrenal insufficiency after the discontinuation of inhaled fluticasone therapy is not indicated due to the apparently low incidence of adrenal insufficiency caused by fluticasone.

CONTEXTLower neurocognitive development scores at age 2 yr have been reported in association with euthyroid hypothyroxinemia during early pregnancy.OBJECTIVEThe objective of this study was to further explore this association with euthyroid hypothyroxinemia during early pregnancy.DESIGNThis was an observational, nested case-control study.SETTINGThe study was conducted at physician offices and prenatal clinics throughout Maine.STUDY SUBJECTSBetween May 2004 and March 2006, TSH was measured in 5734 women in conjunction with second-trimester Down syndrome screening. After completion of pregnancy, free T(4) was measured in stored second-trimester sera from euthyroid women (TSH 0.1-3.5 mIU/ml; n = 5560). Women with free T(4) at the third centile or less (n = 99) were matched with women whose free T(4) was at the 10th to the 90th centile (n = 99).INTERVENTIONSThere were no interventions.MAIN OUTCOME MEASUREBayley Scales of Infant Development (BSID III) were administered to the 198 offspring at age 2 yr. Scores for cognitive, language, and motor development were compared between matched pairs of offspring from the two groups before and after correcting for relevant variables.RESULTSUnadjusted BSID-III scores (cognitive, language, and motor) were lower by about 3% at age 2 yr among offspring of 98 hypothyroxinemic women (cases), reaching borderline significance for cognitive and motor scores. After adjustment for gestational age, the child's age at testing, maternal weight, and education, all differences diminished and became nonsignificant. Scores less than 85 were more frequent among case children but did not reach statistical significance (P = 0.14).CONCLUSIONSIsolated hypothyroxinemia during the second trimester is not associated with significantly lower BSID-III scores at age 2 yr, compared with scores for offspring of matched euthyroxinemic women.

With critical illness, serum testosterone levels fall markedly, whereas estrogen levels rise. Although animal studies suggest adaptive advantages, no prospective model has been available for studies in humans. We hypothesized that coronary artery bypass graft (CABG) surgery would provide such a model by eliciting the same reproductive hormone and other endocrine responses as reported with major nonsurgical illnesses. We further hypothesized that those responses would occur consistently in all CABG patients with predictable time courses, providing reliable windows for prospective studies. In 17 men undergoing CABG, serum levels of reproductive hormones, cortisol, thyroid hormones, and IGF-I were measured before and for up to 5 wk after surgery. Changes in serum levels of reproductive and other hormones were similar to those reported in nonsurgical critically ill patients. Time course for onset, duration, and recovery of reproductive hormone changes were consistent among all patients. A window for studying the testosterone and estrogen responses was established as the first 5 days following CABG. Practical use of this model was demonstrated by evaluating, in another seven men, changes in gonadotroph responsiveness to GnRH following CABG. Finally, to determine whether our findings in CABG could be extended to other surgeries, we demonstrated similar endocrine responses in 12 men following abdominal aortic aneurysm resection. We conclude that patients undergoing CABG surgery provide a useful human model for the prospective evaluation of the reproductive axis responses to acute illness. Other major surgeries are likely to also be suitable for these studies.

OBJECTIVE:First, to identify treatment satisfaction thresholds for interpreting treatment-related changes in vasomotor symptoms, and, second, to determine the doses of desvenlafaxine (DVS) (administered as desvenlafaxine succinate) that effectively provide relief of vasomotor symptoms considered important by menopausal women.DESIGN:Efficacy and treatment satisfaction were assessed in 620 postmenopausal women with moderate to severe vasomotor symptoms participating in a double-blind, placebo-controlled trial and randomly assigned to placebo or 50, 100, 150, or 200 mg DVS. Number and severity of hot flushes and number of nighttime awakenings were recorded in daily diaries for 12 weeks of treatment. At week 12, responses to the Menopause Symptoms Treatment Satisfaction Questionnaire were compared with efficacy results.RESULTS:Greater percentages of participants in the DVS groups reported being "satisfied" or "extremely satisfied" with daytime and nighttime control of hot flushes compared with placebo. The treatment satisfaction threshold, defined as the difference between the average reduction in vasomotor symptoms for women who were "neutral" versus "satisfied," was 1.64 for moderate to severe hot flushes and 0.42 for nighttime awakenings. Statistically significant reductions with 100, 150, and 200 mg DVS exceeded treatment satisfaction threshold results for at least one of these thresholds, and results with 100 mg DVS compared with placebo exceeded both treatment satisfaction thresholds.CONCLUSIONS:Among menopausal women with moderate to severe vasomotor symptoms, the treatment satisfaction thresholds that were meaningful to participants were 1.64 fewer moderate to severe hot flushes per day and 0.42 fewer nighttime awakenings per night. A dose of 100 mg DVS met both of these important vasomotor symptom change thresholds.

Although serum testosterone levels decrease acutely in critically ill patients, estrogen levels rise. We hypothesized that increased rates of aromatization of androgens to estrogens underlie the increase in serum estrogen levels. Eleven men and three women (age 42-69 yr) were prospectively studied before and again after elective coronary artery bypass graft surgery (CABG). Each patient received priming doses of [(14)C]androgen and [(3)H]estrogen that were immediately followed by peripheral infusions for 210 min. Eight men and three women received androstenedione (A(4))/estrone (E(1)) and three men received testosterone (T)/estradiol (E(2)). Adipose tissue biopsies were obtained in another six men before and after CABG to evaluate levels of P450 aromatase mRNA. Serum T levels decreased postoperatively in all 17 men (P < 0.001), whereas E(1) levels rose (P = 0.004), with a trend toward a rise in E(2) (P = 0.23). Peripheral aromatization rates of androgens to estrogens rose markedly in all 14 patients (P < 0.0001). Estrogen clearance rates rose (P < 0.002). Mean serum A(4) levels increased slightly postoperatively (P = 0.04), although no increase in A(4) production rates (PRs) was observed. T PRs decreased in two of three men, whereas clearance rates increased in all three. Adipose tissue P450 aromatase mRNA content increased postoperatively (P < 0.001). We conclude that the primary cause of increased estrogen levels in acute illness is increased aromatase P450 gene expression, resulting in enhanced aromatization of androgens to estrogens, a previously undescribed endocrine response to acute illness. Both increased T clearance and decreased T production contribute to decreased serum T levels. Animal studies suggest that these opposing changes in circulating estrogen and androgen levels may be important to reduce morbidity and mortality in critical illness.

The physiology of the reproductive system changes dramatically with the onset of major illness. The serum testosterone concentrations fall to pre-pubertal levels secondary to a decreased secretion of gonadotropins and a decreased Leydig cell response to luteinizing hormone. At the same time, the serum oestrogen concentration rises as the result of an increased rate of peripheral aromatization. The clinical consequences of these marked changes are not yet well understood. One line of evidence argues for the administration of anabolic steroids (derivatives of testosterone) to critically ill patients to improve their catabolic state. Another line of evidence in animal models suggests that testosterone may suppress the immune system and myocardial function in critical illness. No clinical trials of oestrogen administration to critically ill patients have been reported, although two animal studies suggest that oestrogen may have a positive effect on survival. This chapter reviews changes in the physiology of the reproductive system in major illness as well as current evidence regarding the clinical effects of androgens and oestrogens in critical illness and their potential therapeutic roles.

Annals of the New York Academy of SciencesVolume 519, Issue 1 p. 269-286 Approaches to the Study of GnRH in Humans: Implications for Design of Effective Therapiesa WILLIAM F. CROWLEY JR., WILLIAM F. CROWLEY JR. The Reproductive Endocrine Unit, Vincent Memorial Research Laboratories, Departments of Medicine and Gynecology, Massachusetts General Hospital Boston, Massachusetts 02114Search for more papers by this authorMARCO FILICORI, MARCO FILICORI Department of Reproductive Medicine, University of Bologna 40138 Bologna, ItalySearch for more papers by this authorNANETTE SANTORO, NANETTE SANTORO Department of Reproductive Medicine, University of Bologna 40138 Bologna, ItalySearch for more papers by this authorDANIEL SPRATT, DANIEL SPRATT Division of Endocrinology, University of Vermont, and the Maine Medical Center Portland, Maine 04102Search for more papers by this author WILLIAM F. CROWLEY JR., WILLIAM F. CROWLEY JR. The Reproductive Endocrine Unit, Vincent Memorial Research Laboratories, Departments of Medicine and Gynecology, Massachusetts General Hospital Boston, Massachusetts 02114Search for more papers by this authorMARCO FILICORI, MARCO FILICORI Department of Reproductive Medicine, University of Bologna 40138 Bologna, ItalySearch for more papers by this authorNANETTE SANTORO, NANETTE SANTORO Department of Reproductive Medicine, University of Bologna 40138 Bologna, ItalySearch for more papers by this authorDANIEL SPRATT, DANIEL SPRATT Division of Endocrinology, University of Vermont, and the Maine Medical Center Portland, Maine 04102Search for more papers by this author First published: December 1987 https://doi.org/10.1111/j.1749-6632.1987.tb36303.xCitations: 5 a This research was supported by grants HD15788, HD15080 and RR-1066 from the National Institutes of Health and the Vincent Memorial Research Fund. AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Citing Literature Volume519, Issue1The Terminal Nerve (Nervus Terminalis): Structure, Function, and EvolutionDecember 1987Pages 269-286 RelatedInformation

The combined approach used in studies of GnRH secretion provided a complimentary array of techniques with which to establish the program of amplitude (dose) and frequency of GnRH secretion in the physiologic state. Normative data in men and women were useful in formulating frequency estimates, which could then be applied to the task of replacement of GnRH in deficient (IHH) individuals. Comparison of the results of therapy with these 'ablation-replacement' models then allowed to arrive closer to the true amplitude or dose of exogenous GnRH required to duplicate the physiologic ideal. In addition to providing insight into the neuroendocrine control of reproduction, these applications provided treatment of various reproductive disorders in men and women. Further expansion of the efforts into other potential defects of endogenous GnRH secretion will ultimately uncover those disorders amenable to therapy.