I think the correct answer is 5; FNA does not allow a histological study but a cytological one, therefore questions 1, 2 are eliminated. Question 3 seems to have been put as a filler because it is not relevant. Question 4 could raise doubts if you are not a pathologist but the most logical answer is 5 since papillary carcinoma is the most frequent.

I think [HIDDEN]; FNA does not allow a histological study but a cytological one, therefore questions [HIDDEN]. Question 3 seems to have been put as a filler because it is not relevant. Question 4 could raise doubts if you are not a pathologist but [HIDDEN] since papillary carcinoma is the most frequent.

A 41-year-old man comes to the clinic with a nodule in the right thyroid, a fine needle aspiration is performed. Cytological analysis will allow us:

Distinguish between follicular adenoma or minimally invasive follicular carcinoma.

Identify the areas of capsular or vascular invasion of the follicular carcinoma.

Recognize G-cell hyperplasia associated with familial spinal cancer.

Distinguish between a Hurthle cell tumor and an oxyphilic follicular adenoma.

Identify the typical cytologic features of papillary carcinoma.

Does Hurthle cell lesion/neoplasm predict malignancy more than follicular lesion/neoplasm on thyroid fine-needle aspiration?

Thyroid fine-needle aspiration (FNA) is a standard procedure for the clinical triage of thyroid nodules. The diagnosis of an adequately sampled thyroid FNA is generally grouped into three categories: benign, malignant, and indeterminate. The latter group usually includes follicular neoplasm, follicular lesion, and sometimes a more specific diagnosis such as Hurthle cell neoplasm or follicular lesion/neoplasm with Hurthle cell change. Whether a FNA diagnosis of Hurthle cell lesion/neoplasm (HLN) denotes a worse clinical outcome than follicular lesion/neoplasm (FLN) remains controversial. A cohort of 303 thyroid FNA cases with follow-up thyroidectomy in our institutes was identified, with the follow-up excision diagnosis compared to the FNA diagnosis in order to address this issue. Of this cohort, 87 cases had an FNA diagnosis of HLN while 216 cases had a diagnosis of FLN. Upon excision, the FNA diagnosis of HLN group had 14 cases of goiter/nodular hyperplasia (16%), 46 cases of adenoma (12 follicular adenoma (14%) and 34 cases of Hurthle cell adenoma (39%)), and 27 cases of carcinoma (31%, 12 papillary carcinoma and 15 Hurthle cell carcinoma). The FLN group had 74 cases of goiter/nodular hyperplasia (34.3%), 8 cases of Hashimoto thyroiditis (3.7%), 73 cases of follicular adenoma (33.8%), one case of granular cell tumor, and 60 cases of carcinoma (27.8%, 46 papillary carcinoma, 12 follicular carcinoma, and 1 Hurthle cell carcinoma and 1 parathyroid carcinoma) upon excision. There is no significant difference in predicting cancer between the two cytology diagnosis groups (HLN versus FLN, 31% versus 27.8%, P = 0.5771). When sorting all the cases by the surgical diagnosis, while comparable for age at diagnosis, the cancer group having the higher proportion of male patients than the non-cancer group (28.7% versus 16.7%, P = 0.0259). Hurthle cell carcinoma patients are typically older than patients with other cancer diagnoses (59 versus 44, P = 0.0077). Our results suggest that an FNA diagnosis of HLN does not predict more malignancy than FLN. Males and older patients with a HLN FNA diagnosis carry a higher risk of Hurthle cell carcinoma upon thyroidectomy.

Follicular thyroid cancer

Hurthle cell variant Hurthle cell thyroid cancer is often considered a variant of follicular cell carcinoma. Hurthle cell forms are more likely than follicular carcinomas to be bilateral and multifocal and to metastasize to lymph nodes. Like follicular carcinoma, unilateral hemithyroidectomy is performed for non-invasive disease, and total thyroidectomy for invasive disease. Diagnosis It is difficult to correctly diagnose follicular neoplasms (FNs) on fine-needle aspiration cytology (FNAC) because it shares many cytological features with other mimicking lesions.

Preoperative diagnostic categories of fine needle aspiration cytology for histologically proven thyroid follicular adenoma and carcinoma, and Hurthle cell adenoma and carcinoma: Analysis of cause of under- or misdiagnoses.

Cytologic diagnosis of thyroid follicular adenoma and carcinoma, and Hurthle cell adenoma and carcinoma (FACHAC) is challenging due to cytomorphologic features that overlap with other follicular-patterned lesions. This study was designed to analyze diagnostic categories (DCs) of preoperative fine needle aspiration cytology (FNAC) of histologically proven thyroid FACHACs to evaluate under- or misdiagnoses in FNAC and elucidate potential causes for such phenomena. A total of 104 thyroid nodules with preoperative FNAC which were diagnosed as FACHAC in resection specimens were included in this study. Of these, 66 cases had also undergone thyroid core needle biopsy (CNB); FNAC and CNB DCs were compared in these cases. Various cytologic and histologic parameters were compared between the nodules with different FNAC DCs. After a review of FNAC slides, DCs were re-assigned in 20 (19.2%) out of the 104 cases. Of the 66 cases with CNB diagnoses which were mostly classified as lower DCs in FNAC, 31 (47.0%) were diagnosed as suspicious for a follicular neoplasm in CNB. Cases which were underdiagnosed in FNACs were associated with lower cellularity, predominant macrofollicular pattern, absence of microfollicles arranged in trabecular pattern, and absence of transgressing vessels in cytology smears. High cellularity, microfollicles arranged in trabecular pattern, nucleolar prominence, and large cell dysplasia were more frequently found in malignancy than in benign neoplasm. In conclusion, thyroid FACHACs seem to be under- and misdiagnosed in preoperative FNAC. Innate characteristics of the nodules were associated with under-diagnosis as well as the quality of the FNAC specimens. Certain cytomorphologic features can be helpful in differentiating malignancy among FACHACs.

Thyroid nodules with FNA cytology suspicious for follicular variant of papillary thyroid carcinoma: follow-up and management.

Thyroid nodules diagnosed as follicular neoplasm on fine-needle aspiration biopsy (FNAB) may represent hyperplastic/adenomatous nodules, follicular adenoma or carcinoma, and follicular variants of papillary thyroid carcinoma (FVPTC) on histologic follow-up. In our laboratory, we attempted to identify a subset of cases which showed cellular specimens with focal features (nuclear chromatin clearing, membrane thickening, and rare grooves) suspicious for the follicular variant of papillary thyroid carcinoma. These cases are reported as follicular-derived neoplasms with nuclear features suspicious for FVPTC to distinguish them from those diagnosed as follicular neoplasm. This study documents our experience with 52 cases so diagnosed and followed prospectively with histologic follow-up. A neoplastic nodule was confirmed in 45/52 cases (86%), of which 40 were malignant (77%). FVPTC was identified in 35/52 cases (67%). Four cases were usual papillary carcinoma, 3 were follicular adenoma, 2 were Hürthle-cell adenoma, and 1 was insular carcinoma. In 7 cases, the subsequent histologic findings were nonneoplastic (5 hyperplastic nodules and 2 colloid nodules). Our prospective study shows that in cellular smears from thyroid nodules, a careful search for the nuclear features of papillary carcinoma should be performed, and it is appropriate to diagnose cases as suspicious for FVPTC if the nuclear features of papillary carcinoma are focal. The surgical management of this group may include an intraoperative confirmation of cytologic diagnosis by scrape preparation and/or frozen section in order to avoid a second surgical intervention for completion thyroidectomy.

Computerized Cytological Features for Papillary Thyroid Cancer Diagnosis-Preliminary Report.

Fine needle aspiration cytology (FNAC) is the final diagnosis of thyroid nodules before surgery. It is important to further improve the indeterminate FNAC diagnosis results using computerized cytological features. This retrospective cross-sectional study included 240 cases, of whom 110 had histologic diagnosis of papillary thyroid cancers (PTC), 100 had nodular/adenomatous goiters/hyperplasia (benign goiters), 10 had follicular/Hurthle cell carcinomas, and 20 had follicular adenomas. Morphological and chromatic features of FNAC were quantified and analyzed. The result showed that six quantified cytological features were found significantly different between patients with a histologic diagnosis of PTC and patients with histologic diagnosis of benign goiters in multivariate analysis. These cytological features were used to estimate the malignancy risk in nodules with indeterminate FNAC results. The Area Under the Receiver Operating Characteristics (AUROC) of the diagnostic accuracy with a benign or malignant nature was 81.3% (<ip</i < 0.001), 78.7% (<ip</i = 0.014), and 56.8% (<ip</i = 0.52) for nodules with FNAC results of atypia, which is suspicious for malignancy and follicular neoplasm, respectively. In conclusion, quantification of cytological features could be used to develop a computer-aided tool for diagnosing PTC in thyroid nodules with indeterminate FNAC results.

Hurthle Cell Thyroid Carcinoma -- Evaluation

Non-thyrotoxic thyroid nodules should be evaluated with fine-needle aspiration (FNA) and biopsy. FNA is sufficient to diagnose papillary and anaplastic thyroid cancers. However, FNA cannot distinguish between a benign adenoma and malignant carcinoma for follicular and Hurthle cell tumor types, and this generally requires a thyroid lobectomy or thyroidectomy to perform a surgical pathological evaluation showing capsular invasion, vascular invasion, or infiltration of the thyroid gland to prove invasive cancer.

[Risk factors of malignancy in patients with fine needle aspiration biopsy results interpreted as "suspicious for follicular neoplasm"].

Introduction: Approximately 10% of fine needle aspiration biopsy (FNAB) of thyroid nodules may be verified as "suspicious for follicular neoplasm"; this category involves follicular adenoma, follicular carcinoma, follicular variants of papillary carcinoma and subclass "suspicious for Hurthle cell neoplasm". At present, there is no diagnostic tool to discriminate between follicular adenoma and cancer. Most patients are required surgery to exclude malignant process. The aim: To define factors correlating with risk of malignancy in patients with FNAB of thyroid focal lesions and nodules verified as Bethesda tier IV. Materials and Methods: In this study 110 consecutive patients were included. All patients were operated because of FNAB result "suspicious for follicular neoplasm" of thyroid gland at a single institution from January 2016 until March 2020. From this set, six specific categories were defined and the clinical records for patients were collected: sex, age, presence of oxyphilic cells, diameter of the tumour, presence of Hashimoto disease, aggregate amount of clinical and ultrasonographic features of malignancy according to ATA. Results: In 18 patients (16,3%) thyroid cancer occurred. Most frequent subtype turned out to be papillary cancer (66,6%). In group of benign lesion (92 patients) predominance of follicular adenoma was disclosed - (49%). Age, gender, tumour diameter, aggregate amount of clinical and ultrasonografic factors, presence of Hashimoto disease and fine needle aspiration biopsy result suspicious for Hurthle cell neoplasm did not correspond to increased risk of malignancy. Conclusions: In patients with FNAB results classified as Bethesda tier IV there are no reliable clinical features associated with low risk of malignancy and surgery should be consider in every case as most appropriate manner to exclude thyroid cancer .

Fine-Needle Aspiration Cytology of Noninvasive Follicular Variant of Papillary Thyroid Carcinoma Is Cytomorphologically Distinct From the Invasive Counterpart.

To review a series of noninvasive encapsulated follicular variant of papillary thyroid carcinomas (FVPTCs) in an attempt to further define the role of cytopathology in the diagnosis of noninvasive follicular thyroid neoplasm with papillary-like nuclear features and invasive FVPTC. Surgical pathology cases diagnosed as FVPTC with correlating thyroid fine-needle aspiration (FNA) were identified and divided into two FVPTC groups: noninvasive and invasive. Cytologic diagnoses were compared between them. We identified 23 cases that met the criteria for noninvasive FVPTC and 27 cases that were typical infiltrative FVPTC (n = 16) or encapsulated FVPTC with either capsular and/or lymphovascular invasion (n = 11). Of the noninvasive FVPTC cases, there were four benign lesions, 14 follicular lesions of undetermined significance (FLUS), four follicular neoplasms (FNs), one suspicious case, and no papillary thyroid carcinomas (PTCs). In the invasive FVPTC group, there were no benign cases, four FLUS, three FNs, 12 suspicious cases, and eight PTCs. There is a distinction in the cytologic diagnosis between noninvasive and invasive FVPTC. The invasive subtype was diagnosed by FNA as suspicious for PTC or PTC in nearly 75% of cases, while only one (4%) case for the noninvasive subtype was diagnosed as suspicious for PTC (P < .05).

Macrofollicular Variant of Follicular Thyroid Carcinoma: A Rare Underappreciated Pitfall in the Diagnosis of Thyroid Carcinoma.

<b<iBackground:</i</b Follicular-patterned thyroid nodules predominantly composed of macrofollicular structures without nuclear atypia are generally regarded as benign (i.e., hyperplastic nodules or follicular adenomas). In line with this concept, fine-needle aspiration cytology (FNAC) also assigns a benign connotation to the presence of macrofollicular structures, unless thyrocytes present papillary thyroid carcinoma (PTC)-related nuclear features that raise the possibility of a macrofollicular variant of PTC. However, cases showing macrofollicular architecture, capsular invasion, and no PTC features can also be observed. <b<iMethods:</i</b We describe the clinical, cytological, histological, and molecular genetic features of four cases of encapsulated follicular neoplasms that presented histologically with a predominant (>70%) macrofollicular architecture, but which also showed clear signs of capsular invasion, and thus were classified as macrofollicular variant of follicular thyroid carcinoma (MV-FTC). <b<iResults:</i</b Cytologically, macrofollicular structures were identified in all cases, leading to a benign FNAC diagnosis in three of the four cases. Due to increasing nodule size, thyroidectomy was performed in all cases. Histology showed focal and limited capsular invasion, without vascular invasion. Next-generation sequencing (custom 394 gene panel) of each tumor compared with matched normal DNA revealed a total of 7 somatic variants, including dual (likely biallelic) mutations in the <iDICER1</i gene in 2 patients. The clinical outcome was excellent in all cases. <b<iConclusions:</i</b Similar to the classical minimally invasive follicular thyroid carcinoma, MV-FTC appears to behave indolently. MV-FTC has a high rate of false-negative FNAC results, but MV-FTC is very rare (<0.05% of all thyroidectomies) and apparently has an indolent behavior. Further studies comprising larger series are necessary to better clarify the biology of this diagnostically challenging rare tumor.

Follicular thyroid cancer

Diagnosis It is difficult to correctly diagnose follicular neoplasms (FNs) on fine-needle aspiration cytology (FNAC) because it shares many cytological features with other mimicking lesions. Classification It is impossible to distinguish between follicular adenoma and carcinoma on cytological grounds. If fine needle aspiration cytology (FNAC) suggests follicular neoplasm, thyroid lobectomy should be performed to establish the histopathological diagnosis. Features sine qua non for the diagnosis of follicular carcinoma are capsular invasion and vascular invasion by tumor cells. Still, focuses of the capsular invasion should be carefully evaluated and discriminated from the capsular rupture due to FNA penetration resulting in WHAFFT (worrisome histologic alterations following FNA of thyroid). Follicular carcinoma tends to metastasize to lung and bone via the bloodstream. Papillary thyroid carcinoma commonly metastasizes to cervical lymph nodes.

Follicular Neoplasm of Thyroid Revisited: Current Differential Diagnosis and the Impact of Molecular Testing.

The diagnosis of "follicular neoplasm" (FN) in thyroid cytopathology has a long history that originated not long after the practice of fine-needle aspiration (FNA) of thyroid nodules. From the outset, this interpretive category was intended to convey a set of differential diagnoses rather than a precise diagnosis, as key diagnostic features, such as capsular and vascular invasion, were not detectable on cytology preparations. Cytologic-histologic correlation studies over the past several decades have shown that FN interpretation can be applied to the spectrum of nonneoplastic tumors to carcinomas. Most tumors classified as FN include follicular adenoma, follicular carcinoma, noninvasive follicular thyroid tumor with papillary-like nuclear features, and follicular variant of papillary thyroid carcinoma. Less common entities that may be classified as FN on FNA include hyalinizing trabecular tumor (HTT), poorly differentiated thyroid carcinoma, medullary carcinoma, and nonthyroidal lesions such as parathyroid tissue, paraganglioma, and metastatic tumors. Advances in our ability to detect characteristic molecular alterations (eg, GLIS gene rearrangements for hyalinizing trabecular tumor) in FNA samples may assist in the identification of some of these entities. In this review, we summarize the pathophysiology, history, and evolution of the terminology and the current differential diagnosis according to the recently published 2022 World Health Organization classification, molecular testing, and management of nodules classified as FN.

Utility of frozen section analysis on follicular lesions of the thyroid.

The experience of one surgeon (R.H.) with intraoperative frozen sections (FS) performed on thyroid nodules over a 10-year period was studied to assess the utility of FS in follicular thyroid lesions. One hundred and ten patients with dominant or solitary nodules demonstrating a follicular growth pattern were evaluated. The FS slides and subsequently the permanent sections of the nodules were reviewed by the pathologists in the study (M.P.B., VAL.) without knowledge of the original diagnoses. Our results indicate: (1) if the FS was definitively benign (58 patients), the final diagnosis was benign [these lesions consisted of adenomatous nodule, nodular goiter, follicular adenoma, and Hürthle cell adenoma); (2) if an FS diagnosis of malignancy was rendered (4 patients), it was confirmed on permanent sections (follicular variant of papillary carcinoma in all 4); and (3) if the FS diagnosis was deferred (48 patients), the final diagnosis was benign in all but 10 (21 %) (of these 10, 6 had minimally invasive follicular carcinoma [2 of the Hürthle cell type], and 4 had follicular variants of papillary carcinoma). Overall, sensitivity, specificity, and accuracy rates for FS diagnoses were 29, 100, and 91%. Because unilateral lobectomy may be acceptable therapy for well-differentiated thyroid cancers, and because the efficiency of FS evaluation in diagnosing malignancy is low (only 4 malignancies of 110 total patients were diagnosed at FS, or 3.6% overall), we conclude that in this era of cost-containment, FS is not useful in the evaluation of follicular thyroid nodules identified preoperatively as follicular lesions by fine-needle aspiration cytology. Several recommendations concerning the 3 categories of FS diagnosis (i.e., definitively benign, definitively malignant-especially the follicular variant of papillary carcinoma-and deferred) are also put forward.

International Classification of Diseases for Oncology

M8331/3 Follicular adenocarcinoma, well differentiated (C73.9) Follicular carcinoma, well differentiated M8332/3 Follicular adenocarcinoma, trabecular (C73.9) Follicular carcinoma, trabecular Follicular adenocarcinoma, moderately differentiated FOlloicular carcinoma, moderately differentiated M8333/0 Microfollicular adenoma, NOS (C73.9) Fetal adenoma M8333/3 Fetal adenocarcinoma M8334/0 Macrofollicular adenoma (C73.9) Colloid adenoma M8335/3 Follicular carcinoma, minimally invasive (C73.9) Follicular carcinoma, encapsulated M8336/0 Hyalinizing trabecular adenoma (C73.9) (M8337/3)Insular carcinoma (C73.9) M8340/3 Papillary carcinoma, follicular variant (C73.9) Papillary adenocarcinoma, follicular variant Papillary and follicular adenocarcinoma Papillary and follicular carcinoma M8341/3 Papillary microcarcinoma (C73.9) M8342/3 Papillary carcinoma, oxyphilic cell (C73.9) M8343/3 Papillary carcinoma, encapsulated (C73.9)

Thyroid Cancer -- Histopathology

FTC: The histological features of FTC can be highly variable, from a well-differentiated follicular pattern to a poorly differentiated pattern with marked nuclear atypia, absence of follicles, extensive capsular or vascular invasion, and solid growth. The latter changes are associated with a poor prognosis. [27] As described above, features that are characteristic of PTC should be absent. Differentiating a follicular carcinoma from a benign follicular adenoma can only be made based on extracapsular and/or vascular invasion. FTC is further classified as minimally invasive, encapsulated, angioinvasive, and widely invasive, depending on the extent of invasion. Hurthle cell carcinoma: This is characterized by the occurrence of eosinophilic oxyphilic cells with abundant cytoplasm (oncocytes) and prominent nucleoli. [28]

Adenomatoid nodules are the main cause for discrepant histology in 234 thyroid fine-needle aspirates reported as follicular neoplasm.

According to several large studies, the surgical pathologist renders a non-neoplastic diagnosis in ∼20-40% of thyroid fine-needle aspiration (FNA) cases reported as follicular neoplasm. This study analyzes the cause of this poor correlation between cytology and histology. Cases consisting of oncocytic (Hurthle) cells were excluded from study. During the study period from January 1996 to April 2010, histologic follow-up was available for 234 of 670 cases (34.9%) reported as follicular neoplasm on ultrasound-guided thyroid FNA. Sonographic and Doppler data were available in all cases and included nodule location, size, echogenicity, and vascularity. Of the 234 aspirates with follow-up, surgical pathology reported 130 cases (55.6%) of follicular adenoma, 15 cases (6.4%) of follicular carcinoma, 14 cases (6.1%) of follicular variant of papillary carcinoma, and 75 cases (32.3%) of nodular goiter. Recuts of those index nodules reported as nodular goiter were examined independently by two pathologists using the 2× objective lens. Adenomatoid nodule was defined as an insufficiently encapsulated "blue" nodule of increased nuclear density when compared with the surrounding thyroid. Of the 75 cases reported as nodular goiter, 60 index nodules (80%) fulfilled the described criteria for adenomatoid nodule, while 15 did not. In conclusion, adenomatoid nodules are the main cause of poor histologic correlation with follicular neoplasm reported by FNA. If "increased nuclear density at scanning magnification" were adopted by surgical pathologists as the major diagnostic criterion for follicular adenoma rather than encapsulation, noncorrelated cases would be reduced from 32 to 6.4%.

Noninvasive follicular thyroid neoplasm with papillary-like nuclear features

History Patients in the distant past with this lesion would have been regarded as showing signs of having a benign lesion, a follicular adenoma. However, over time and with additional evaluation and molecular testing, these lesions came to be regarded as showing features of a papillary thyroid carcinoma because of their papillary carcinoma type nuclei. Thus, the "follicular variant" of a tumor that normally shows a papillary architecture and papillary nuclear features was named. Over the years, those cases that do not show invasion of either the capsule of the tumor or the vessels in the capsule, have been shown to behave in an indolent fashion, with only rare reported cases of metastatic disease.

Oncocytoma

Symptoms Salivary gland oncocytomas are most common in ages 70–80, females, the parotid gland (85–90%), and are firm, slowly growing, painless masses of less than 4 cm. They may be bilateral. Thyroid oncocytoma Thyroid oncocytomas can be benign (adenomas) or malignant (carcinomas). Also known as Hürtle cell tumours. Grossly, oncocytic adenomas are encapsulated, solid nodules with a characteristic brown cut surface. The gross appearance of a minimally invasive oncocytic carcinoma is indistinguishable to that of an adenoma, while widely invasive oncocytic carcinomas are obviously invasive macroscopically and display pervasive vascular invasion with multifocal involvement of the thyroid gland. There are no reliable cytologic features which distinguish oncocytic adenomas from carcinomas and the only criterion for a diagnosis of malignancy is the identification of transcapsular or vascular invasion.

Thyroid adenoma

Papillary adenomata are very rare. Differential diagnosis A thyroid adenoma is distinguished from a multinodular goiter of the thyroid in that an adenoma is typically solitary, and is a neoplasm resulting from a genetic mutation (or other genetic abnormality) in a single precursor cell. In contrast, a multinodular goiter is usually thought to result from a hyperplastic response of the entire thyroid gland to a stimulus, such as iodine deficiency. Careful pathological examination may be necessary to distinguish a thyroid adenoma from a minimally invasive follicular thyroid carcinoma.

Computed tomography of the thyroid

Thyroid cancers Epidemiology Primary thyroid carcinomas include papillary, follicular, medullary, and anaplastic carcinomas. Lymphoma and metastasis of other primary malignancies to the thyroid gland represent a minority of thyroid carcinomas. Differentiated thyroid carcinomas (DTCs) originate from follicular epithelial cells and encompass PTCs and follicular thyroid carcinomas, including the Hurthle cell variant of follicular carcinoma. DTCs have an excellent prognosis and fortunately represent the majority of thyroid carcinomas. PTCs and follicular thyroid carcinomas represent 88 % and 8 %, respectively, of all thyroid malignancies. Medullary thyroid carcinoma arises from neuroendocrine C-cells and has a good prognosis. Anaplastic carcinoma is an aggressive undifferentiated tumour that usually affects the elderly and tends to have a worse prognosis. Role of imaging

Suspicious thyroid nodules 4 cm require a diagnostic lobectomy regardless of their benign fine needle aspiration results.

The diagnostic accuracy of fine needle aspiration biopsy (FNAB) seems limited in large thyroid nodules with Bethesda Cat. 2 result. We aimed to determine the incidence of carcinoma with benign cytology and the reason for the high false-positive rate in thyroid nodules ≥4 cm. The records of 103 patients with thyroid nodules ≥4 cm with preoperative cytological diagnosis of Bethesda Cat. 2 who underwent thyroidectomy were consecutively reviewed. Characteristics between patients with malignant vs. benign pathology were compared. Forty patients (38.8%) had malignancy. Malignancy was subclassified into follicular variant of papillary thyroid carcinoma (43%), minimally invasive follicular thyroid carcinoma (20.0%), and minimally invasive Hurthle cell thyroid carcinoma (10.9%). Patients with malignant cytology had significantly more suspicious ultrasound findings than those with benign cytology (p = 0.001). Preoperative FNAB showed high false-negative rates in patients with thyroid nodules ≥4 cm with benign cytology. These nodules have a high malignancy rate with suspicious ultrasound findings.

Thyroid Adenoma -- Evaluation

Fine needle aspiration (FNA) has ultimately been used in evaluating a thyroid nodule with suspicious radiology features, especially in patients with a high risk of malignancy. It should be mentioned that fine-needle aspiration may not provide a definite diagnosis in all cases. In patients with thyroid adenoma, the cytological sample has organized follicular epithelial cells. On the other hand, aspiration can show follicular cells with abnormal architecture and atypia. These patients are characterized as having atypia of undetermined significance. [26] A benign thyroid adenoma is confirmed only after ruling out capsular and vessel invasion in the final histological examination done by pathologists after a partial or total thyroidectomy operation. Genetic testing has also helped a lot in predicting the risk of thyroid cancer, and it has frequently been used in the final decision-making of proceeding to surgical intervention of removing a thyroid nodule versus not. [27]

Thyroid adenoma

Careful pathological examination may be necessary to distinguish a thyroid adenoma from a minimally invasive follicular thyroid carcinoma. Management Most patients with thyroid adenoma can be managed by watchful waiting (without surgical excision) with regular monitoring. However, some patients still choose surgery after being fully informed of the risks. Regular monitoring mainly consists of watching for changes in nodule size and symptoms, and repeat ultrasonography or needle aspiration biopsy if the nodule grows. For patients with benign thyroid adenomata, thyroid lobectomy and isthmusectomy is a sufficient surgical treatment. This procedure is also adequate for patients with minimally invasive thyroid cancer. When histological examination shows no signs of malignancy, then no further intervention is required. These patients should continue to have their thyroid hormone status regularly checked. References External links Thyroid cancer

Follicular Adenoma -- Differential Diagnosis

Follicular adenomas typically present as a solitary nodule; thus, all other likely causes of a solitary thyroid nodule should be considered. [5] [4] [27] Follicular carcinoma Other benign neoplasms Hurtle cell adenoma Non-invasive follicular tumor with papillary like nuclear features (NIFTP) Other carcinomas Papillary thyroid carcinoma Medullary carcinoma Thyroiditis: rarely can present as a nodule

Over a multiyear time frame, an international consensus project was undertaken to re-define the pathological criteria for the encapsulated follicular variant of papillary thyroid carcinoma. Based on a rigorous review of the literature and a multicentre review of many cases with long-term follow-up (a minimum of 10 years) together with molecular analysis of some tumors, this working group has determined that tumors previously classified as the encapsulated follicular variant of papillary carcinoma—without any evidence of capsular or vascular invasion, provided that the entire periphery of the tumor (capsule if encapsulated or periphery if well circumscribed) has been sampled—can be reclassified as noninvasive follicular thyroid neoplasms with papillary-like nuclear features. There are several major inclusion and exclusion criteria.

Hürthle cell

A Hürthle cell is a cell in the thyroid that is often associated with Hashimoto's thyroiditis as well as benign and malignant tumors (Hürthle cell adenoma and Hürthle cell carcinoma, formerly considered a subtype of follicular thyroid cancer). This version is a relatively rare form of differentiated thyroid cancer, accounting for only 3-10% of all differentiated thyroid cancers. Oncocytes in the thyroid are often called Hürthle cells. Although the terms oncocyte, oxyphilic cell, and Hürthle cell are used interchangeably, Hürthle cell is used only to indicate cells of thyroid follicular origin.

Fine needle aspiration cytology of thyroid follicular neoplasm: cytohistologic correlation and accuracy.

This study evaluated the accuracy of fine needle aspiration cytology (FNAC) in cases of follicular neoplasm (FN) on the basis of histologic diagnosis, and reviewed the cytologic findings of FN according to the FNAC. Among the 66 cases diagnosed with thyroid FN by FNAC during the 7-year period from 2003 to 2009, 36 cases that had undergone thyroid surgery were available for review. Cytologic diagnosis was compared with the histologic diagnosis of each case. Among the 36 cases with a cytologic diagnosis of thyroid FN, histologic diagnosis was as follows: 20 follicular adenomas (55.6%), 3 Hurthle cell adenomas (8.3%), 2 follicular carcinomas (5.6%), 8 nodular goiters (22.2%), 2 papillary carcinomas (5.6%), and 1 Hashimoto's thyroiditis (2.8%), resulting in a diagnostic accuracy of FNAC for thyroid FN of 69.5%. This study shows that FNAC for thyroid FN is a useful primary screening method because when FN is diagnosed by FNAC, the rate of FN histologic diagnosis is relatively high, however, adequate sampling and experience is a prerequisite for this procedure.

Papillary thyroid cancer

Several variants are recognized, although classic papillary thyroid carcinoma is the most frequent: microscopic-follicular variant, diffuse-sclerosing variant, tall-cell variant, columnar-cell variant, hobnail variant, and others. The encapsulated-follicular variant, specifically when noninvasive, has been newly reclassified as the noninvasive follicular thyroid neoplasm with papillary-like nuclear features. Although papillary carcinoma has a propensity to invade lymphatics, it is less likely to invade blood vessels. These kinds of tumors are most commonly unencapsulated, and they have a high tendency to metastasize locally to lymph nodes, which may produce cystic structures near the thyroid that are difficult to diagnose because of the paucity of malignant tissue. Furthermore, papillary tumors may metastasize to the lungs and produce a few nodules or the lung fields may exhibit a snowflake appearance throughout.

Follicular thyroid cancer

Initial treatment If follicular cells are found on cytological testing, it is common to carry out hemithyroidectomy to distinguish between follicular adenoma and follicular carcinoma on histopathological examination, proceeding to completion thyroidectomy and postoperative radioiodine ablation where carcinoma is confirmed. This way total thyroidectomy is not carried out unnecessarily. Thyroidectomy is invariably followed by radioiodine treatment at levels from 50 to 200 millicuries following two weeks of a low iodine diet (LID). Occasionally treatment must be repeated if annual scans indicate remaining cancerous tissue. Some physicians favor administering the maximum safe dose (calculated based on a number of factors), while others favor administering smaller doses, which may still be effective in ablating all thyroid tissue. I-131 is used for ablation of the thyroid tissue. Minimally invasive thyroidectomy has been used in recent years in cases where the nodules are small.

Exclusion criteria 1) Any invasion. 2) The presence of any other papillary thyroid carcinoma variant (examples would include tall cell, columnar cell, cribriform morular, diffuse sclerosing, etc.). 3) True papillary structures (a fibrovascular core surrounded by neoplastic cells). While originally limited to <1%, newer data suggests no papillary structures should be allowed. 4) Psammoma bodies. These are calcified remnants of papillary structures, and thus if a psammoma body is present anywhere within the tumor (in the correct location), then a NIFTP cannot be diagnosed. 5) Tumor necrosis: If there is true tumor necrosis not associated with a fine needle aspiration. 6) Increased mitoses: If there are ≥3 mitoses per 10 high-power fields, then this category cannot be used.

Hürthle cell

and growth pattern of the tumor cannot be used to determine malignancy, although larger tumors have higher incidence of malignancy, Hürthle cell adenomas and carcinomas have to be separated by the presence, in the case of carcinomas, or absence, in the case of adenomas, of both capsular invasion and vascular invasion. Tumors displaying only capsular invasion tend to behave less aggressively than those with vascular invasion. Hürthle cell carcinomas are characterized as either minimally invasive or widely invasive tumors. While the minimally invasive or encapsulated carcinoma is fully surrounded by a fibrous capsule, the widely invasive carcinoma shows extensive area of both capsular and vascular invasion with the leftover capsule typically difficult to identify. Classification is important since widely invasive tumors can have outcomes with a 55% mortality rate.

Thyroid cancer

Thyroid cancers can be classified according to their histopathological characteristics. These variants can be distinguished (distribution over various subtypes may show regional variation): Papillary thyroid cancer (75 to 85% of cases) – is more often diagnosed in young females compared to other types of thyroid cancer and has an excellent prognosis. It may occur in women with familial adenomatous polyposis and in patients with Cowden syndrome. A follicular variant of papillary thyroid cancer also exists. Newly reclassified variant: noninvasive follicular thyroid neoplasm with papillary-like nuclear features is considered an indolent tumor of limited biologic potential. Follicular thyroid cancer (10 to 20% of cases) – occasionally seen in people with Cowden syndrome. Some include Hürthle cell carcinoma as a variant and others list it as a separate type.

Papillary and follicular carcinoma M8341/3 Papillary microcarcinoma (C73.9) M8342/3 Papillary carcinoma, oxyphilic cell (C73.9) M8343/3 Papillary carcinoma, encapsulated (C73.9) M8344/3 Papillary carcinoma, columnar cell (C73.9) Papillary carcinoma, tall cell M8345/3 Medullary carcinoma with amyloid stroma (C73.9) Parafollicular cell carcinoma C cell carcinoma M8346/3 Mixed medullary-follicular carcinoma (C73.9) M8347/3 Mixed medullary-papillary carcinoma (C73.9) M8350/3 Nonencapsulated sclerosing carcinoma (c73.9) Nonencapsulated sclerosing adenocarcinoma Nonencapsulated sclerosing tumor Papillary carcinoma, diffuse sclerosing M8360/1 Multiple endocrine adenomas Endocrine adenomatosis M8361/0 Juxtaglomerular tumor (C64.9) Reninoma M8370/0 Adrenal cortical adenoma, NOS (C74.0) Adrenal cortical tumor, benign Adrenal cortical tumor, NOS M8370/3 Adrenal cortical carcinoma (C74.0) Adrenal cortical adenocarcinoma Adrenal cortical tumor, malignant


Kallman's syndrome or Morsier's syndrome is a congenital insufficiency associated with hypogonadotropic hypogonadism due to a deficit in GnRH hormone production. Repeated injections of GnRH are performed to restore fertility.

A 22-year-old boy with hyposmia presents with lack of development of secondary sexual characteristics and infertility. Bilateral testicular volume of 4 mL. Analytically, FSH 1.2 U/L (vn 5-15); LH 0.6 U/L (vn 3-15); testosterone 100 ng/diu (vn 300-1200), prolactin normal. Indicate the treatment you will propose to achieve fertility:

Monthly intramuscular administration of triptorelin.

Intramuscular administration of FSH and LH once a week.

Hypogonadism, galactorrhoea and hyper-prolactinaemia: Evaluation of pituitary gonadotrophins reserve before and under bromocriptine.

Twenty patients with hypogonadism (19 women with amenorrhoea and 1 man with impotence and infertility), galactorrhoea and hyper-prolactinaemia (range: 36 to 344 ng/ml) were studied. The radiological study of the sella turcica, including in all cases hypocycloidal tomograms, allowed classification of the patients into 3 groups: group I (n = 4) had a grossly enlarged sella turcica, group II (n = 12) had localized alterations indicating the probable existence of a prolactin-secreting microadenoma ("microdeformation") while group III patients presented no radiological abnormality. Before treatment, all the patients were submitted to a complete evaluation of the function of their anterior pituitary, including the LH and FSH responses to iv administration of Gn-RH. All the group I patients had low basal LH levels and a blunted response to Gn-RH. The basal LH and in response to Gn-RH were normal in most of the group II patients and in all of the group III patients. An exaggerated FSH response to Gn-RH was observed in 6/12 patients with microdeformation (group II) but not in groups I and III patients. A low LH and a blunted LH response to Gn-RH is highly suggestive of the existence of a pituitary prolactin-secreting adenoma in case of amenorrhoea and hyper-prolactinaemia patients; a normal response does not however rule out such a diagnosis. The reasons for a exaggerated FSH response to Gn-RH in patients with suspected prolactin-secreting microadenoma remain to be investigated though this pattern can also occur in other cases of amenorrhoea. Hence the Gn-RH test might contribute to the assessment of the hypothalamo-pituitary axis of patients with hyper-prolactinaemia. Six patients treated for 4 months with bromocriptine (CB-154) were submitted to re-evaluation of their pituitary gonadotrophins reserve. All the women experienced restoration of menses with 39 days of treatment and the male patient regained potency. It was observed that bromocriptine treatment and subsequent normalized prolactin levels in the 4 group II women tested were associated with normalization of their previously exaggerated FSH response to Gn-RH; LH responses were also diminished in these cases. These data are compatible with the hypothesis that hyper-prolactinaemia per se could interfere with the endogenous secretion of Gn-RH at the hypothalamic level. In one patient with grossly enlarged sella turcica and a previous lack of an LH and FSH response to Gn-RH, bromocriptine treatment restored a normal gonadotrophins response, confirming that, in this case, the alteration of this response was indeed due to a prolonged lack of endogenous Gn-RH secretion.

[The effects of bromocriptine on anovulatory patients with high LH and euprolactinemia].

It is well known that an acute administration of Bromocriptine (dopamine agonist) suppresses the serum LH level either in normal women or in women with polycystic ovary syndrome, in whom the serum LH level is elevated. The present study was carried out to examine the effectiveness of Bromocriptine on anovulatory women with a high LH level (serum LH greater than 30 mIU/ml). Bromocriptine was administered for 3 months, 5 mg daily, to 9 anovulatory women with euprolactinemia (serum PRL less than 25 ng/ml). Ovulation was observed by their BBT charts. Before and after the treatment of Bromocriptine, FSH, LH and PRL secreting capacities were tested by LHRH and TRH injection. Also, estrone, estradiol and testosterone levels were measured before and after the Bromocriptine administration. Resting levels of LH, FSH and PRL were 45.4 +/- 11.0 mIU/ml, 11.4 +/- 3.0 mIU/ml, and 14.3 +/- 4.7 ng/ml (M +/- SD), respectively, before the treatment. As a result of the treatment, the LH level was markedly decreased to 27.3 +/- 14.5 (M +/- SD, P less than 0.05), and PRL decreased to 3.76 +/- 4.2 ng/ml (M +/- SD, P less than 0.005). On the other hand, FSH did not show a marked change. The responsiveness of LH to LHRH before the treatment showed a marked increase, which was suppressed by Bromocriptine. However, FSH showed no change. The responsiveness of PRL to TRH was suppressed by Bromocriptine. Serum estrone, estradiol and testosterone levels before the treatment were 115.5 +/- 76.7 pg/ml, 93.7 +/- 61.0 pg/ml and 0.809 +/- 0.209 ng/ml (M +/- SD), respectively, which showed no significant change after the treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Desogestrel

of FSH and testosterone levels. A previous study by the same authors found that increasing the dosage of desogestrel from 300 μg/day to 450 μg/day resulted in no further suppression of gonadotropin concentrations. The addition of a low dose of 50 or 100 mg/week intramuscular testosterone enanthate after 3 weeks increased testosterone levels and further suppressed LH and FSH levels, to the limits of assay detection (i.e., to undetectable or near-undetectable levels), in both the 150 μg/day and 300 μg/day desogestrel groups. Upon cessation of treatment, levels of LH, FSH, and testosterone all recovered to baseline values within 4 weeks.

Clinical and hormonal response to short-term intermittent versus continuous oral bromocriptine in hyperprolactinemic women.

OBJECTIVE -- To determine if intermittent oral bromocriptine administration could be a useful therapeutic alternative in infertile hyperprolactinemic women. DESIGN -- Open, randomized and prospective study. SETTING -- Outpatient infertility clinic of a third-level medical institution. PATIENTS -- Fourteen low-income women, 23 to 36 years of age with anovulatory infertility (1-13 years in duration) secondary to hyperprolactinemia (>35 ng/mL). Endocrine profile ruled out anovulation of other origin. INTERVENTIONS -- After a control period of 30 days, seven women (group 1) received daily oral bromocriptine (2.5-10.0 mg/day) continuously during two consecutive 30-day periods (T-1 and T-2), and seven women (group 2) received oral bromocriptine only from day 1 to 15 of each 30-day period of treatment. Morning blood samples were drawn similarly during the three periods on days 6 to 8, 13 to 15, and 21 to 23. MAIN OUTCOME MEASURES -- FSH, LH, and prolactin were determined in all samples, estradiol only in samples of days 6 to 8 and 13 to 15, and progesterone exclusively between days 21 and 23. Mean serum prolactin levels during the control period were similarly elevated in groups 1 and 2. A marked decrease occurred during period T-1 (P < .004) and further during period T-2 (P < .05) in both groups, but at no time were significant intergroup differences documented. During the control period all women had a serum progesterone < 3.0 ng/mL (<9.54 nmol/L); during period T-2 it was > or = 3.0 ng/mL in three and five women of groups 1 and 2, respectively. Over the following 10 months of treatment, two and three normal pregnancies and deliveries ensued in groups 1 and 2, respectively. CONCLUSION -- The intermittent use of oral bromocriptine may indeed be a useful therapeutic approach in treating infertile hyperprolactinemic women.

Hypopituitarism

Basal tests Levels of LH/FSH may be suppressed by a raised prolactin level, and are therefore not interpretable unless prolactin is low or normal. In men, the combination of low LH and FSH in combination with a low testosterone confirms LH/FSH deficiency; a high testosterone would indicate a source elsewhere in the body (such as a testosterone-secreting tumor). In women, the diagnosis of LH/FSH deficiency depends on whether the woman has been through the menopause. Before the menopause, abnormal menstrual periods together with low estradiol and LH/FSH levels confirm a pituitary problem; after the menopause (when LH/FSH levels are normally elevated and the ovaries produce less estradiol), inappropriately low LH/FSH alone is sufficient. Stimulation tests with GnRH are possible, but their use is not encouraged.

[Effect of pulsatile GnRH therapy on pituitary-testicular axis function in male patients with pituitary stalk interruption syndrome].

To evaluate the efficacy of pulsatile gonadotropin-releasing hormone (GnRH) therapy in male patients with pituitary stalk interruption syndrome (PSIS). Fourteen male PSIS patients, who had received subcutaneous pulsatile GnRH therapy for at least four weeks at Peking Union Medical College Hospital from April 2014 to September 2015, were included in the study. Serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone level, testicular volume and sperm in ejaculation were measured. After treatment for four weeks, subjects with serum LH≥1.24 U/L were classified as"good response group", and others were classified as"poor response group". All patients were born by breech delivery and presented with absent pubertal development. Laboratory findings showed combined pituitary hormone deficiency in all patients. Pituitary stalk interruption syndrome was diagnosed based on MRI findings. Totally 11 out of 14 patients showed good response to pulsatile GnRH therapy. Their LH level increased from 0.32 (0.15, 0.61) U/L to 4.34(2.52, 7.39)U/L(P<0.001), FSH from 0.84 (0.30, 1.50) U/L to 7.12 (4.53, 10.09) U/L(P<0.001); serum testosterone level from 0 (0, 0.45) nmol/L to 2.46 (0.56, 11.45) nmol/L (P=0.004) and testicular volume from 2.0 (2.0, 4.0) ml to 4.0 (3.0, 6.0) ml (P=0.005). Sperm was detected in seminal samples after treatment for 8 weeks in two patients and for 12 weeks in one patients. Three out of 14 patients showed poor response to pulsatile GnRH therapy. Pulsatile GnRH therapy can effectively establish the pituitary-testicular axis function for most patients with pituitary stalk interruption syndrome, indicating enough reserve of gonadotrophs in the pituitary.

Testosterone administration inhibits gonadotropin secretion by an effect directly on the human pituitary.

Testosterone (T) administration slows LH pulse frequency in man, presumably by an effect on the hypothalamic GnRH pulse generator, but it also may have a direct action on the pituitary. To determine if T does indeed affect gonadotropin secretion by acting directly on the pituitary, we studied the effect of T on GnRH-stimulated gonadotropin secretion. Six men with hypogonadotropic hypogonadism were treated with physiological doses of GnRH (5 micrograms every 2 h, sc by automatic infusion pump) for 6 weeks. Once their gonadotropin levels were normal, the men received a supraphysiological dosage of T enanthate (200 mg, im, weekly for 8 weeks) in addition to GnRH. They then received GnRH alone for a final 8-week period. Blood sampling was performed every 10 min for 8 h at the end of each of the three study periods. T administration suppressed the mean serum LH level to about 50% of the value during GnRH alone [18 +/- 2 (+/- SE) vs. 37 +/- 2 micrograms/L; P less than 0.05] and suppressed the mean serum FSH level to about 30% of the value during GnRH alone (39 +/- 6 vs. 128 +/- 28 micrograms/L; P less than 0.05). Eight weeks after stopping T, while continuing GnRH alone, serum LH and FSH levels were similar to those at the end of the first period of GnRH administration. The mean LH response to GnRH was reduced during T administration (17 +/- 3 micrograms/L) compared to that during the initial period of GnRH alone (31 +/- 4 micrograms/L; P less than 0.05). Serum T and estradiol levels were in the low normal range after GnRH alone before T administration (11 +/- 2 nmol/L and 105 +/- 17 pmol/L, respectively) and increased to just above the normal adult ranges after 8 weeks of T administration (36 +/- 5 nmol/L and 264 +/- 49 pmol/L, respectively). These results demonstrate that T and/or its metabolites inhibit LH and FSH secretion by a GnRH-independent mechanism, probably directly on the pituitary gland, in man.

Gynecology_Novak

Brain imaging (MRI is the gold standard) to exclude  Pituitary microadenoma  Pituitary macroadenoma  Other abnormal brain mass Hypothyroidism  Exclude secondary causes  Treat condition  Supplement with thyroid hormone if indicated  Spontaneous ovulation will occur when thyroid function normalizes  Treat underlying condition  When prolactin normalizes, spontaneous ovulation should occur Anovulation Normal or high day 3 FSH and LH Ovarian disorders (see Figure 30.3) Low LH, FSH, TSH, GH, ACTH High serum prolactin levels Abnormal TSH or T4Low FSH, LH, E2 Hypothalmic disorders Thyroid disease Hyperprolactinemia Panhypopituitarism Assess and treat condition Repeat test to exclude false positive Elevated prolactin If a pituatary microadenoma is diagnosed  Bromocriptine or cabergoline to normalize prolactin level  Spontaneous ovulation should occur when prolactin is normal Anorexia  Medical and psychiatric assessment  Treat condition  Aim to increase BMI to allow spontaneous

Gonadotropin-releasing hormone agonist

Agonists do not quickly dissociate from the GnRH receptor. As a result, initially there is an increase in FSH and LH secretion (so-called "flare effect"). Levels of LH may increase by up to 10-fold, while levels of testosterone generally increase to 140 to 200% of baseline values. However, after continuous administration, a profound hypogonadal effect (i.e. decrease in FSH and LH) is achieved through receptor downregulation by internalization of receptors. Generally this induced and reversible hypogonadism is the therapeutic goal. During the flare, peak levels of testosterone occur after 2 to 4 days, baseline testosterone levels are returned to by 7 to 8 days, and castrate levels of testosterone are achieved by 2 to 4 weeks. Following cessation of exogenous GnRH agonist it takes 5 to 8 days before normal gonadotropin secretion is completely restored.

Testicular function of actively immunized male rats with LH releasing hormone (LHRH): a possible role of prolactin on regulation of spermatogenesis.

The effect of testosterone propionate (TP) on the recovery of spermatogenesis was compared in 3 types of experimentally induced gonadotropin-deficient rats; 1. hypophysectomized rats, 2. rats actively immunized to LHRH and 3. hypophysectomized and immunized rats bearing a pituitary isograft. In order to immunize animals to LHRH, deamidated LHRH conjugated with BSA (LHRH-BSA) was injected intradermally to male rats 4 times at 2 week intervals and additional booster injections continued once a month. Anti-LHRH titer was the highest on the 12th week and the titer remained at a relatively high levels thereafter. A remarkable decrease in testicular weight and testosterone production was achieved in 10 weeks associated with a drop in serum LH and FSH levels. In long term immunized rat (LIM rats) which had been immunized for more than 3 months, testicular atrophy advanced to a similar extent to that in long term hypophysectomized rats (HX rats). The administration of TP (1 mg/day) sc for 30 days restored spermatogenesis in LIM rats. The simultaneous administration of anti-LH and -FSH sera in addition to TP did not affect the restoration of spermatogenesis in LIM rats. The same TP treatment in HX rats, however, failed to restore spermatogenesis. Spermatogenesis was reinitiated after TP treatment if immunized-hypophysectomized rats received a pituitary isograft. Though the serum PRL level in LIM rats was one fifth of that in normal rats, a 2.5-fold rise in the PRL level was observed after TP treatment. These results suggest that PRL is involved in the process of spermatogenesis.

Treatment of hypogonadotropic hypogonadal male patients with the luteinizing hormone-relasing hormone (LH-RH) anolog D-Ser(TBU)6 EA10 LH-RH: transient disappearance of gonadotropin stimulation.

We have studied the effect of prolonged treatment with a long-acting luteinizing hormone-releasing hormone (LH-RH) analog (D-Ser-(TBU)6 EA10 LH-RH in six patients with isolated gonadotropin deficiency. Before treatment, all subjects responded to LH-RH (100 microgram intravenously [IV]); one responded immediately, and five after 5 daily infusions of LH-RH (200 microgram). Treatment by LH-RH analog (348 microgram every 2 days with a nasal spray for 90 or 120 days) is only efficient for 1 month; a consistent increase in serum LH and a slight increase in testosterone (T) were observed in all patients, but no increase of serum follicle-stimulating hormone (FSH) was detectable. Then a paradoxical effect appeared: LH and T levels returned to the basal values. Moreover, this treatment induced refractoriness of the pituitary to LH-RH for several months after the end of treatment. The appearance of antibodies to LH-RH and LH-RH analog was eliminated. A pituitary response was obtained in three patients when a new LH-RH stimulation was repeated 7 and 11 months after the end of treatment. The mechanism of this pituitary desensitization is discussed.

InternalMed_Harrison

Although a variety of treatment regimens are used, 1000–2000 IU of hCG or recombinant human LH (rhLH) administered intramuscularly three times weekly is a reasonable starting dose. Testosterone levels should be measured 6–8 weeks later and 48–72 h after the hCG or rhLH injection; the hCG/rhLH dose should be adjusted to achieve testosterone levels in the mid-normal range. Sperm counts should be monitored on a monthly basis. It may take several months for spermatogenesis to be restored; therefore, it is important to forewarn patients about the potential length and expense of the treatment and to provide conservative estimates of success rates. If testosterone levels are in the mid-normal range but the sperm concentrations are low after 6 months of therapy with hCG alone, FSH should be added. This can be done by using hMG, highly purified urinary hFSH, or recombinant hFSH. The selection of FSH dose is empirical. A common practice is to start with the addition of 75 IU FSH three times

Testicular leydig cell tumor presenting as primary infertility.

A 29-year old male and his wife presented with an 18 month history of primary infertility. History and initial investigations suggested no major female pathologic component but a semen analysis revealed azoospermia. There was no history of any sexual dysfunction and neither partner was receiving any medication. Clinical examination revealed normal secondary sexual characteristics. Both testicles were of normal consistency with a volume of approximately 15 ml but a 4 x 2 cm mass was palpable at the lower pole of the left testis. Laboratory investigations revealed: serum testosterone 37.1 nmol/l (NV:10.0-38.0 nmol/l), LH<0.3 U/L (NV:3.0-12.0 U/L), and FSH <0.1 IU/L (NV:3.0-11.0 U/L). Serum b-HCG, aFP, LDH, oestradiol and inhibin levels were within the normal range. A repeated semen analysis confirmed azoospermia. Testicular ultrasound demonstrated a well-defined hypoechoic mass, measuring 31 x 23 x 17 mm and containing several flecks of calcification, arising from the lower pole of the left testis. A left orchidectomy was performed. Macroscopical histopathological examination revealed a single firm dark brown nodule 2.8 cm in diameter arising from the lower pole of the testis. The tumor distended the capsule of the testis without extending through it. Microscopical examination was consistent with a Leydig cell tumor. Computerised tomography of the chest, abdomen and pelvis was normal. Six months later, laboratory investigations revealed a serum testosterone of 14.3 nmol/l, an LH of 5.4 U/L and an FSH of 4.3 U/L, respectively. A repeated semen analysis was normal: volume 1.8 ml(2-10 ml), count 124 x 10(6) (20-350 x 10(6)), motility 80%(>60%), abnormal forms <15%(<15%). Three months later his wife was pregnant. In summary, our patient presented with azoospermia, secondary to a Leydig cell tumor, which was reversible after removal of the tumor.

[Effects of a new analogue of LH-RH, D-Ser(TBU)6- EA10-LH-RH, on gonadotropin liberation in males (author's transl)].

Effects on the secretion of gonadotropins by D-Ser (TBU)6-EA10-LH-RH were investigated in 7 male volunteers without known endocrine disturbances. One week after subcutaneous injection of 100 mug of LH-RH the probands were given 5 mug of the LH-RH analogue subcutaneously into the abdominal wall. LH, FSH and testosterone concentrations were estimated in the serum and compared with each other at varying intervals after each injection. LH-RH caused a marked increase of the LH content in serum after 20 minutes with a maximum after 40 minutes. The effect of the analogue occurred with a delay. After 40 minutes an LH level was reached which still persisted 6 hours later. Contrary to LH there were considerable individual differences in serum FSH levels. In the initial phase after injection of LH-RH and LH-RH analogue that increase of the FSH level in serum was almost parallel. However, the analogue showed a marked depot effect. Serum concentrations of testosterone showed no significant changes after administration of the releasing hormones. D-Ser(TBU)6-EA10-LH-RH is approximately 20 times effective as LH-RH. A dose of 5 mug is effective for 6-8 hours.

Spontaneous and GnRH-provoked gonadotropin secretion and testosterone response to human chorionic gonadotropin in adolescent boys with thalassaemia major and delayed puberty.

To elucidate whether the cause of sexual maturation arrest in thalassaemia is of gonadal or pituitary etiology, 10 males with thalassaemia and delayed puberty and 10 with constitutional delay of growth and pubertal maturation (CSS) were extensively studied. Their spontaneous nocturnal gonadotropin secretion and gonadotropin response to intravenous 100 micrograms gonadotropin-releasing hormone (GnRH) were evaluated. Circulating testosterone concentration and clinical response were evaluated after 3 days, 4 weeks and 6 months of intramuscular administration of human chorionic gonadotropin (HCG) (2500 U/m2/dose). Thalassaemic boys had significantly lower circulating concentrations of testosterone compared to those with constitutional delay of growth and sexual maturation (CSS) at the same pubertal stage. Short- and long-term testosterone response to administrations of HCG was markedly decreased in thalassaemic boys. After 6 months of HCG administration 50 per cent (5/10) of the boys did not show significant testicular enlargement or genital changes. Despite the low circulating concentrations of testosterone, none of the patients had high basal or exaggerated gonadotropin response to gonadotropin releasing hormone (GnRH) stimulation. Luteinizing hormone (LH) peak responses to GnRH were significantly lower as compared to controls. Follicle-stimulating hormone (FSH) peak responses to GnRH did not differ among the two study groups. The mean nocturnal LH and FSH secretion was significantly decreased in all thalassaemic boys as compared to boys with CSS at the same pubertal stage (testicular volume). These data proved that hypogonadotropic hypogonadism is the main cause of delayed/failed puberty in adolescents with thalassaemia major. MRI studies revealed complete empty sella (n = 5), marked diminution of the pituitary size (n = 5), thinning of the pituitary stalk (n = 3) with its posterior displacement (n = 2), and evidence of iron deposition in the pituitary gland and midbrain (n = 8) in thalassaemic patients, denoting a high incidence of structural abnormalities (atrophy) of the pituitary gland. Moreover, in many of the thalassaemic boys, the defective testosterone response to long-term (6 months) HCG therapy denoted significant testicular atrophy and/or failure secondary to siderosis. It appears that testosterone replacement might be superior to HCG therapy in these patients. This therapy should be introduced at the proper time in these hypogonadal patients to induce their sexual development and to support their linear growth spurt and bone mineral accretion.

Effect of a new LH-RH analogue (D-Ser(TBU)6-EA10-LH-RH) on gonadotrophin and gonadal steroid secretion in men.

The effect of a new analogue of the gonadotrophin-releasing hormone LH-RH, D-Ser(TBU)6-EA10-LH-RH, on the secretion of LH, FSH, as well as testosterone, oestradiol, HGH, prolactin, TSH, and cortisol was studied in normal men. The same subjects were injected intravenously in 4-day intervals with 1.0, 2.5, 5.0, and 10.0 mug of this substance. A significant LH but no FSH release was seen after doses of 1.0 and 2.5 mug LH-RH analogue, while after 5.0 and 10.0 mug dose-dependent increases of LH and imposed elevations of FSH were observed. Peak levels of LH were reached after 30 min, those of FSH after intravenous injection after 120 min. LH and FSH remained elevated for 8-10 h. LH peak levels after 5 mug of LH-RH analogue were comparable to those seen after injection of 100 mug of the decapeptide LH-RH. Following the release of LH and FSH after doses of 5.0 and 10.0 mug LH-RH analogue, there was a late stimulating effect in testosterone and oestradiol secretion. HGH, TSH, prolactin, and cortisol were not influenced by the LH-RH analogue.

Comparison of detection of normal puberty in boys by a hormonal sleep test and a gonadotropin-releasing hormone agonist test.

The magnitude of sleep-related gonadotropin rise required to activate pubertal gonadal function is not established. Our objective was to determine the normal relationship between sleep-related pubertal hormone levels and pituitary-testicular responsiveness to a GnRH agonist (GnRHag) test across the pubertal transition. DESIGN/SETTING AND PARTICIPANTS: We conducted a prospective study in a General Clinical Research Center with healthy 9- to 15-yr-old volunteer boys. INTERVENTIONS included overnight blood sampling followed by leuprolide acetate injection (10 μg/kg). LH, FSH, and testosterone levels were evaluated. LH levels during sleep and post-GnRHag rose steadily during the late prepubertal years. Sleep peak LH correlated highly with the LH response to GnRHag across groups (r = 0.913). A sleep peak LH level of at least 3.7 U/liter predicted pubertal testicular activation with 100% accuracy. LH of at least 14.8 and at least 19.0 U/liter 4 h after GnRHag, respectively, predicted puberty with 100% sensitivity/94% specificity and 100% specificity/94% sensitivity. Overweight pubertal boys had transiently prolonged responses to GnRHag. FSH rose during both waking and sleeping hours during the prepubertal years, and all pubertal boys had an FSH level of at least 0.9 U/liter awake and at least 1.2 U/liter asleep. Sleep LH was more closely related than FSH to testicular size. These data suggest that a critical LH level during sleep (≥3.7 U/liter) heralds the onset of pubertal virilization and that this level is predictable by LH of at least 14.8-19 U/liter 4 h after GnRHag. These data also suggest that LH stimulation of testicular androgen production plays a role in stimulating testicular tubule growth once a critical level of FSH is achieved.

[Increased and prolonged release of lh and fsh on intravenous administration of a synthetic analogue of lh-rh [d-ser(tbu)6-ea10-lh-rh] in healthy men of various age groups (author's transl)].

Healthy male subjects of various age groups respond to the administration of D-Ser(TBU)6-EA10-LH-RH, an analogue of LH-RH substituted in positions 6 and 10, by a prolonged and increased release of LH and FSH. Increased serum concentrations of LH and FSH were observed 20 minutes after intravenous administration of the compound. Maximum concentrations of LH and FSH were seen after 60, and 60 to 240 minutes, respectively. Serum concentrations of both gonadotropins remained elevanted for up to 8 hours after the administration of 10 microgram of the LH-RH analogue. A dose response relationship was observed with regard to the serum concentrations of LH and FSH over the range of 1.25 to 5.0 microgram of the LH-RH analogue. The administration of 10 or 20 microgram of the compound, however, did not cause a further rise in plasma FSH, although the release of LH was further enhanced.

Daily testosterone and gonadotropin levels are similar in azoospermic and nonazoospermic normal men administered weekly testosterone: implications for male contraceptive development.

Weekly intramuscular administration of testosterone esters such as testosterone enanthate (TE) suppresses gonadotropins and spermatogenesis and has been studied as a male contraceptive. For unknown reasons, however, some men fail to achieve azoospermia with such regimens. We hypothesized that either 1) daily circulating serum fluoroimmunoreactive gonadotropins were higher or testosterone levels were lower during the weekly injection interval, or 2) monthly circulating bioactive gonadotropin levels were higher in nonazoospermic men. We therefore analyzed daily testosterone and fluoroimmunoreactive gonadotropin levels as well as pooled monthly bioactive and fluoroimmunoreactive gonadotropin levels in normal men receiving chronic TE injections and correlated these levels with sperm production. After a 3-month control period, 51 normal men were randomly assigned to receive intramuscular TE at 25 mg (n = 10), 50 mg (n = 9), 100 mg (n = 10), 300 mg (n = 10), or placebo (n = 12) weekly for 6 months. After 5 months of testosterone administration, morning testosterone and fluoroimmunoreactive follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels were measured daily for a 1-week period between TE injections. In addition, fluoroimmunoreactive and bioactive FSH and LH levels were measured in pooled monthly blood samples drawn just before the next TE injection. In the 100-mg and 300-mg TE groups, mean monthly fluoroimmunoreactive FSH and LH levels were suppressed by 86%-97%, bioactive FSH and LH levels by 62%-80%, and roughly half the subjects became azoospermic. In the 1-week period of month 6, daily testosterone levels between TE injections were within the normal range in men receiving placebo, or 25 or 50 mg of weekly TE, but were significantly elevated in men receiving 100 or 300 mg of weekly TE. At no point during treatment, however, were there significant differences in daily testosterone or fluoroimmunoreactive gonadotropin levels, or monthly bioactive gonadotropin levels between men achieving azoospermia and those with persistent spermatogenesis. This study, therefore, demonstrates that neither monthly nor daily differences in serum testosterone, or fluoroimmunoreactive or bioactive gonadotropins explain why some men fail to completely suppress their sperm counts to zero with weekly TE administration. Innate differences in the testicle's ability to maintain spermatogenesis in a low-gonadotropin environment may explain persistent spermatogenesis in some men treated with androgen-based contraceptive regimens.

Further acquisitions on gonadal function in bromocriptine treated hyperprolactinemic male patients.

The diurnal variation of plasma total and free testosterone (tT and fT) and the gonadotropinemic response to LH-RH were evaluated in a group of hyperprolactinemic impotent males with pituitary microprolactinoma before and during therapy with bromocriptine, a well known dopamine agonist drug. Before treatment, basal levels not only of tT but also of fT were decreased and the diurnal variation of both tT and fT was absent. Moreover, the LH-RH test showed a delay in the LH response peak, together with normal basal levels of LH. Bromocriptine therapy caused normalization of both the secretion response of LH to LH-RH and of the secretion pattern of tT and of fT (basal levels and diurnal variation) besides a significant decrease in PRL levels and an improvement in sexual function. The possible effects of high plasma levels of PRL at various levels of the hypothalamus-pituitary-testicular axis are discussed.

Gonadotropin-releasing hormone insensitivity

Diagnosis When suspected on the basis of the clinical presentation or physical findings, the diagnosis of GnRH insensitivity should be confirmed biochemically. The diagnosis requires the following findings: The demonstration of prepubertal serum concentrations of sex steroid hormones (serum testosterone less than 100 ng/dL [3.5 nmol/L] in males or serum estradiol less than 20 pg/mL [73 pmol/L] in females). Inappropriately low or normal serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) concentrations (usually less than 4 to 5 international units/L) rather than the high concentrations expected with primary gonadal failure. Otherwise normal anterior pituitary function.

Gonadotropin-releasing hormone (GnRH) analog suppression renders polycystic ovarian disease patients more susceptible to ovulation induction with pulsatile GnRH.

Pulsatile GnRH administration consistently restores normal reproductive hormone levels and ovulation in women with hypogonadotropic hypogonadism, but is less effective in those with polycystic ovarian disease (PCOD). We pharmacologically created a hypogonadotropic condition with a GnRH analog (GnRH-A) in six women with PCOD to investigate the role of deranged gonadotropin secretion in PCOD and to improve the response to pulsatile GnRH ovulation induction. Before GnRH and GnRH-A treatment the women with PCOD had increased LH pulse frequency [one pulse every 55 +/- 2 (+/- SE) min; P less than 0.05] and LH pulse amplitude (10.9 +/- 1.4 U/L; P less than 0.05) compared to normal women in the follicular phase of their menstrual cycle. Each PCOD woman completed one cycle of pulsatile GnRH administration for ovulation induction before (pre-A cycles; n = 6) and one or two cycles after (post-A cycles; n = 9) GnRH-A administration [D-Ser(tBu)6-Des,Gly10-GnRH; 300 micrograms, sc, twice daily for 8 weeks]. Pulsatile GnRH (5 micrograms/bolus) was given at 60-min intervals using a Zyklomat pump. Daily blood samples were drawn during the pulsatile GnRH ovulation induction cycles for the determination of serum LH, FSH, estradiol (E2), progesterone, and testosterone, and pelvic ultrasonography was done at 1- to 4-day intervals. Mean (+/- SE) serum LH levels were elevated during the pre-A cycle (49.2 +/- 3.1 IU/L) and decreased to normal levels during the post-A cycles (19.6 +/- 1.4 IU/L; P less than 0.0001). Mean testosterone concentrations were lower during the post-A cycles [88 +/- 2 ng/dL (3.1 +/- 0.1 nmol/L)] than during the pre-A cycles [122 +/- 3 ng/dL (4.2 +/- 0.1 nmol/L); P less than 0.0001]. In the follicular phase of the post-A cycles E2 levels were significantly lower [81 +/- 5 pg/mL (300 +/- 20 pmol/L) vs. 133 +/- 14 pg/mL (490 +/- 50 pmol/L); P less than 0.0001], preovulatory ovarian volume was smaller (24.6 +/- 2.0 vs. 31.4 +/- 2.4 cm3; P less than 0.01), and the FSH to LH ratio was higher (0.56 +/- 0.03 vs. 0.16 +/- 0.01) than in the pre-A cycle, suggesting more appropriate function of the pituitary-gonadal axis. Excessive LH and E2 responses to pulsatile GnRH administration in the early follicular phase of the pre-A cycle were abolished in the post-A cycles.(ABSTRACT TRUNCATED AT 400 WORDS)

Pituitary and testicular response to LH-RH and to a long-acting analogue (D-leu-6-LH-RH-ethylamide).

The LH, FSH and testosterone response to 50 microgram i.v. LH-RH and to 2.5, 5.0, 10.0, and 20.0 microgram i.m. D-Leu-6-LH-RH-ethylamide was studied in 6 subjects with normogonadotrophic, idiopathic oligozoospermia. All injections were given between 8:00 and 9:00 a.m. at weekly intervals. Blood samples were collected before and 30 and 45 minutes after injection of LH-RH, and before and 2, 4, 6, 12, and 24 hours after D-Leu-6-LH-RH-ethylamide injections. Serum levels of LH, FSH, and testosterone were measured by triplicate by R.I.A. LH and FSH responses to LH-RH showed peak values at 30 minutes, whereas following injections of D-Leu-6-LH-RH-ethylamide, maximal values were recorded between 4 and 6 hours and were higher than those obtained with LH-RH. A significant rise of serum testosterone levels was observed after all stimuli, with peak values 45 minutes after LH-RH and 4 to 6 hours after D-Leu-6-Lh-RH-ethylamide injections. The testosterone levels obtained following LH-RH and different doses of the analogue did not differ significantly from one another. The same sequence of maximal LH and FSH values was obtained after injections of LH-RH and of D-Leu-6-LH-RH-ethylamide, particularly at doses of 10.0 and 20.0 microgram. This suggests that the gonadotrophin response to these agents would be a true reflection of the individual mode of pituitary response.

Prolactinoma presenting as a failed vasectomy reversal.

To present a case of prolactinoma presenting as a failed vasectomy reversal. Case report. University-affiliated teaching hospital. A 46-year-old male with severe oligospermia after bilateral vasovasostomy and his 31-year-old female partner who had normal cycles. Bromocriptine, carbegoline, and l IVF. Correction of hyperprolactinoma, improved semen analysis, and pregnancy achieved by assisted reproductive technologies. Semen analysis showing low volume (0.65 mL) and severe oligospermia (16 sperm) with zero motility on presentation. Endocrine evaluation showed prolactin of 650 ng/mL, T 0.37 ng/mL, and FSH 2.0 mIU/mL. A head CT scan showed a 1.2 cm pituitary adenoma. This was managed initially with bromocriptine, but due to side effects he was switched to carbegoline. In 1 month his PRL decreased to 16.9 ng/mL. Testosterone and FSH normalized. Repeat semen analysis after 5 months showed a volume of 4.5 mL and a concentration of 15 million/mL with 1% motility. Antisperm antibodies were positive. Because of antisperm antibodies and oligoasthenospermia, intracytoplasmic sperm injection with ejaculated sperm and, later, testicular extraction, were attempted without success. Donor sperm was eventually used. This is the first reported case of prolactinoma as a cause of infertility after vas reversal and demonstrates that not all cases of suspected failed vasectomy reversals are due to recurrent obstruction.

Reduction of follicle-stimulating hormone (FSH) secretion in FSH-producing pituitary adenoma by bromocriptine.

An FSH-secreting pituitary adenoma was demonstrated in a 32-yr-old man who presented with unilateral optic atrophy without any clinical or laboratory evidence of hypogonadism. Semen analysis was normal, although basal FSH levels were markedly elevated (greater than 80 mIU/ml). He had normal plasma LH levels and no other detectable endocrine abnormalities. Administration of GnRH elicited delayed and sustained FSH and brisk LH responses. Administration of TRH resulted in TSH and PRL responses and unexpected FSH and LH elevations. Two surgical operations resulted in temporary reduction of plasma FSH levels, but it increased later concomitant with CT demonstration of tumor growth. After pituitary irradiation, no reduction in FSH levels occurred. A single dose of 5 mg bromocriptine elicited a significant reduction in FSH levels from 137 to 64 mIU/ml. Long term treatment with 15 mg/day bromocriptine resulted in further reduction of FSH level, to 36.4 mIU/ml, without any change in tumor size. This finding implies that bromocriptine could be an adjunctive therapy or an alternative to other modes of treatment in patients with these rare tumors.

Hypothalamic-pituitary-gonadal axis function in pubertal male and female siblings with glucocorticoid-treated nonsalt-wasting 3 beta-hydroxysteroid dehydrogenase deficiency congenital adrenal hyperplasia.

We report pubertal maturation and dynamic studies of gonadotropin and gonadal hormone secretion in long term glucocorticoid-treated siblings with nonsalt-wasting classic adrenal and gonadal 3 beta-hydroxysteroid dehydrogenase (3 beta HSD) deficiency. The 18-yr-old female siblings spontaneously developed thelarche and menarche at 10 and 12 yr, respectively, and manifested irregular menses, hirsutism, and polycystic ovaries at 17 yr. The 16-yr-old male sibling spontaneously developed secondary sex characteristics at age 11 yr and exhibited Tanner IV-V pubic hair, a 6.5 x 3.0-cm surgically repaired penis, and enlarged nonnodular testes. Overnight (2200-0700 h) plasma gonadotropin (every 20 min) and gonadal steroid levels (every 2 h) under ACTH adrenal suppression revealed the following. In the male sibling, there were overall normal Tanner V male LH (3-21 mIU/mL) and FSH (1.2-13 mIU/mL) levels, normal peak frequency and amplitude of LH (70 +/- 62 min and 15 +/- 3 mIU/mL, respectively) and FSH (65 +/- 28 min and 13 +/- 3 mIU/mL), and low normal Tanner V testosterone (T) levels (11.4-17.9 nmol/L). In the female sibling, there were normal follicular phase range LH (10-28 mIU/mL) and FSH (5.1-17.2 mIU/mL) levels, normal peak frequency and amplitude of LH (96 +/- 17 min and 22 +/- 4.5 mIU/mL, respectively) and FSH (62 +/- 27 min, 13 +/- 4 mIU/mL), and early follicular phase estradiol (E2) levels (100-170 pmol/L). The LH-releasing hormone-stimulated LH response was in the normal adult range in the male and normal for the early follicular phase in the female. In contrast, ACTH and adrenal delta 5-steroid responses to CRH administration were elevated in each sibling. Gonadal suppression via Norlutin administration (30 mg/day for 3 days) after prolonged adrenal suppression by dexamethasone resulted in suppression of dehydroepiandrosterone (DHEA) and E2 in the female and DHEA and T in the male. Gonadal stimulation via hCG administration (5000 IU/day for 3 days, im) during continuous adrenal suppression resulted in a low E2 response in the female (200 pmol/L; control, 295-660 pmol/L) and a low T response in the male (15.3 nmol/L; control, 17-39 nmol/L), whereas delta 5-17-hydroxypregnenolone and DHEA levels rose 2- to 4.7-fold in each sibling. In conclusion, despite partial gonadal 3 beta HSD deficiency, the dynamics of gonadotropin and gonadal hormone secretion in these siblings indicate the absence of increased LH secretion, in contrast to the markedly increased ACTH secretion resulting from adrenal 3 beta HSD deficiency.(ABSTRACT TRUNCATED AT 400 WORDS)

Kallmann syndrome

Treatment for both males and females with KS/CHH normally consists of one of three options which can be used for both hormone replacement therapy and/or fertility treatment. Sex hormone replacement (testosterone or oestrogen & progesterone). Gonadotropin therapy (medications that replicate the activity of FSH and LH). GnRH pulsatile therapy. Hormone replacement therapy The method and dose of treatment will vary depending on the individual being treated. Initial treatment is normally made with lower doses in younger patients in order to develop the secondary sexual characteristics before adult doses are reached.

Serum hormone concentrations during treatment with multiple rising doses of recombinant follicle stimulating hormone (Puregon) in men with hypogonadotropic hypogonadism.

To study increases of serum FSH and gonadal response in gonadotropin-deficient men treated with recombinant FSH (Puregon; NV Organon, Oss, The Netherlands). An open, prospective, multiple rising dose study in which volunteers received single daily IM doses of recombinant FSH for 3 weeks. The dose administered was increased at weekly intervals: the first 7 days, 75 IU/d; the subsequent 7 days, 150 IU/d; and the last 7 days, 225 IU/d. Nine men suffering from isolated gonadotropin deficiency or panhypopituitarism. Immunoreactive FSH, LH, inhibin, T, and androstenedione. Serum immunoreactive FSH (median) rose in accordance with the recombinant FSH doses administered from 0.5 mIU/mL (range < 0.05 to 1.9 mIU/mL) at baseline to 4.3 mIU/mL (range 2.0 to 8.5 mIU/mL), 8.4 mIU/mL (range 4.9 to 17.8 mIU/mL), and 13.6 mIU/mL (5.6 to 28.4 mIU/mL) after 1, 2, and 3 weeks of medication, respectively. The elimination half-life of recombinant FSH was 48 +/- 5 hours (mean +/- SD), which was slightly longer than that reported after single dose administration of recombinant FSH (32 +/- 12 hours). The bioactivity of recombinant FSH was reflected by serum inhibin levels, which rose from 116 U/L (range 34 to 356 U/L) at baseline to 350 U/L (range 63 to 1,109 U/L) at day 22. However, serum FSH and inhibin levels did not correlate when compared after 1, 2, and 3 weeks of recombinant FSH administration. Serum immunoreactive LH, T, androstenedione, and E2 were 0.2 mIU/mL (range < 0.05 to 0.7 mIU/mL [conversion factor to SI unit, 1.0]), 58 ng/dL (range < 12 to 222 ng/dL [conversion factor to SI unit, 0.0347]), 14 ng/dL (range 6 to 115 ng/dL [conversion factor to SI unit, 0.0349]), and 14 pg/mL (range < 14 to 16 pg/mL [conversion factor to SI unit, 3.67]), respectively, at baseline and remained unchanged during the entire treatment period. These data indicate that recombinant FSH treatment increases serum FSH in a dose-proportional fashion, increases inhibin secretion, and lacks intrinsic LH activity.

Pituitary function in normoprolactinaemic infertile men receiving bromocriptine.

A double blind trial of bromocriptine 7.5 mg daily versus placebo was carried out in ten infertile men. Pretreatment basal plasma prolactin, thyroid stimulating hormone (TSH) testosterone and luteinizing hormone (LH) concentrations were normal, but plasma follicle-stimulating-hormone (FSH) was raised in four individuals. After 4 months treatment with bromocriptine a significant fall in plasma prolactin was observed (P less than 0.01), both under basal conditions and following thyroid stimulating hormone releasing hormone (TRH). Basal plasma gonadotrophin, testosterone and thyroid stimulating hormone (TSH) concentrations did not alter. No change in sperm density, volume or motility was noted. However an apparent fall in the peak plasma LH (but not FSH) response to gonadotrophin releasing hormone (LHRH) was observed in patients receiving bromocriptine. This reduction in plasma LH responsiveness was significant when compared with the baseline response (P less than 0.05) but failed to reach significance when compared with the placebo response. It is concluded that prolonged bromocriptine therapy in normoprolactinaemic men does not suppress FSH secretion, and any reduction in plasma LH responsiveness to LHRH is not accompanied by a significant fall in plasma testosterone.

Pituitary response to steroid replacement therapy in fertile, subfertile and infertile stallions after castration.

Recent studies in our laboratory investigating plasma gonadotrophin concentrations before and after castration indicate that the hypothalamic-pituitary axis is not the original site of dysfunction in stallions with idiopathic infertility. In the present study, fertile, subfertile and infertile stallions were subjected to replacement therapy with oestradiol and testosterone 1 year after castration to investigate hypothalamic-pituitary axis function further. Fertile (n=5), subfertile (n=3) and infertile (n=2) castrated stallions of Light horse breeds, aged 11-23 years, were given either oestradiol cypionate or testosterone propionate for 28 days during the breeding season. Oestradiol cypionate in cottonseed oil (30 mg; 6 mg ml(-1)) was administered i.m. at 2 day intervals starting in May for 28 days. Eight weeks after the last oestradiol cypionate injection, testosterone propionate in vegetable oil (85 mg; 8.5 mg ml(-1)) was administered i.m. at 2 day intervals for 28 days. Heparinized blood samples were taken from the jugular vein three times a week from 3 weeks before the start of oestradiol cypionate treatment until 4 weeks after the last testosterone propionate injection. Saline or 25 microg GnRH in 1 ml saline were administered to the stallions on days 24 and 25, respectively, of the 28 day steroid treatments. Jugular blood samples were collected periodically through a catheter from 60 min before saline or GnRH injection until 420 min after injection. The plasma samples were stored at -20 degrees C until analysed for plasma LH, FSH, oestradiol and testosterone concentrations by validated radioimmunoassay. Exogenous steroid treatment increased plasma oestradiol and testosterone concentrations to concentrations close to normal circulating values (oestradiol: 49 pg ml(-1); testosterone: 1.3 ng ml(-1)) in all the groups. There were no significant differences in plasma LH or FSH concentrations among the groups during any of the treatment periods. Oestradiol treatment significantly increased (P < 0.05) LH concentrations, whereas testosterone treatment decreased LH concentrations, although the difference was not significant. Oestradiol treatment significantly decreased FSH concentrations (P < 0.05), whereas testosterone treatment significantly increased FSH concentrations (P < 0.05). There were no differences in LH and FSH responses to GnRH challenge among the three groups of stallions. In conclusion, the results of the present study indicate that the hypothalamic-pituitary axes in these subfertile and infertile stallions were not the original sites of dysfunction. Further studies at the testicular level are required.

Results of three-times-per-week long-term administration of a luteinizing hormone-releasing hormone (LHRH) analog, D-Ser-(TBU)6-LHRH-(EA)10 in primary amenorrhea.

The effectiveness of a luteinizing hormone (LH)-releasing hormone (LHRH) analog, D-Ser-(TBU)6-LHRH-(EA)10 (Hoe 766), applied intranasally in a 3 days-per-week regimen, was assessed in four patients with hypogonadotropic or normogonadotropic primary amenorrhea by measuring LH, follicle-stimulating hormone (FSH), and estradiol (E2) levels before and 4 hours after its application and by observing the clinical effects of these hormones on the genital tract. The LH response increased progressively over the first 21 days (nine applications) in three of the four patients; it was subsequently reduced but never abolished throughout the study, which was terminated with the 25th application on the 59th day. Basal values of E2 increased until the 12th to 14th day (fifth or sixth application) and then showed a definite decline despite the continuing increase in LH response. FSH release attained a maximum by the second to fourth application and its magnitude of response remained remarkably stable thereafter. The clinical response did not correspond to the serum levels of E2. It is postulated that the development of LH unresponsiveness is due to desensitization of the receptors by the analog. The poor response of the genital tissues to the normal levels of E2 and the subsequent decrease in E2 levels, which occurred despite increasing LH responsiveness, are attributed to an inhibitory action of the analog on E2 biosynthesis in the ovary and on E2 receptors in the genital organs.

Hypogonadotropic hypogonadism

Administration of FSH is required to induce spermatogenesis by acting on Sertoli cells. FSH is required for maintaining the production of high numbers of good quality sperm. Gonadotropin therapy in HH men usually is able to generate enough sperm for fertility to occur, however sperm count is still lower than normal. In the female, the goal for gonadotropin therapy is to obtain ovulation. This is obtained with FSH treatment followed by hCG or LH to trigger ovulation. FSH will stimulate granulosa cells for follicular maturation while LH will act on luteal cells to produce steroids aiding follicular maturation and preparing the endometrium for pregnancy. For hyperprolactinaemia-caused AHH, dopamine agonists are used to improve GnRH secretion. Dopamine binds to D2 receptors on lactotrophs within the anterior pituitary This results in the inhibition of secretion of prolactin resulting in less direct and indirect inhibition of GnRH secretion.