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Recent studies have shown that C natriuretic peptide is produced from granulosa cells, increasing cumulative guanosine monophosphate (cGMP) production by affecting cumulus cells through natriuretic peptide receptors. It is suggested that produced cGMP maintains the transport of oocytes via the gap junctions and leads to a continuous increase in cyclic adenosine monophosphate (cAMP) levels in the oocyte. An important role of increased internal cAMP levels in the oocyte is shown to suppress meiotic progression.
Deoxyribonucleic acid studies in animals have shown that expression of the natriuretic peptide precursor increases during the periovulatory period and shows that this increase decreases rapidly after luteinizing hormone / human chorionic gonadotropin (hCG) stimulation.Human studies have shown that after ovulation induction, the CNP level in follicular fluid decreases following ovulatory dose of hCG.Polycystic ovary syndrome (PCOS) is the most common endocrine disease in the reproductive period, characterized by hyperandrogenism, oligo-anovulation, and polycystic ovarian morphology on ultrasonography, and in an animal study investigating the relationship between CNP and PCOS, serum CNP levels were increased in polycystic ovary syndrome.CNP serum level is thought to show differences between healthy women and women with polycystic ovary syndrome.
In this prospective study, a total of 60 patients are planed to be included. PCOS group will be consisted of 30 women and control group will include 30 healthy women with regular menstruation aged between 18-40 years old. PCOS diagnosis will be made according to Rotterdam criteria.
Age and body mass index of all participants will be recorded. BMI will be calculated by dividing weight by height in square meters. Then morning fasting venous blood samples will be taken from the patients between 2nd-5th day of menstruation for both groups. All blood samples will be centrifuged on the day of collection. Sera will be aliquoted into 1.5 mL Eppendorf (Eppendorf, Milano, Italy) tubes, and will be kept at -80°C until the day of CNP test. For the PCOS patients describing oligo/anovulation, after excluding pregnancy, progesterone withdrawal bleeding will be created and then the patients will be evaluated. Serum levels of LH, FSH, estradiol, thyroid stimulating hormone (TSH), prolactin (PRL), androstenedione, dehydroepiandrosterone sulfate (DHEAS), total testosterone, free testosterone, sex hormone binding globulin (SHBG), total cholesterol (TC), triglyceride (TG), high density lipoprotein (HDL), low density lipoprotein (LDL), glucose and insulin levels will be analyzed. For insulin sensitivity, homeostatic model of insulin resistance (HOMA-IR) will be used and it will be calculated by the formula: HOMA-IR ¼ fasting blood glucose (mg/dL)fasting insulin (mIU/mL)/405. Free androgen index will be calculated by the formula 100x (Total testosteron/SHBG).
Serum CNP levels of the patients will be analyzed by an enzyme-linked immunosorbent (ELISA) assay for human C-type natriuretic peptide in accordance with the manufacturer's instructions (SEA721Hu, ELISA Kit for Human C-Type Natriuretic Peptide, Wuhan USCN Business Co., Ltd., Cloud-Clone Corp., CCC, USA).
Data will be analyzed using Statistical Packege for Social Sciences software (SPSS v15, SPSS Inc, Chicago, IL, USA). Independent t-test will be used to compare the parameters with normal distribution. Parameters that don't fulfill the parametric test assumptions will be compared using Mann-Whitney U test. Correlation of CNP with other parameters will be analyzed using Spearman's rank correlation test. Receiver operating characteristic (ROC) curve will be used to evaluate diagnostic sensitivity and specificity of CNP for PCOS. P values less than 0.05 will be regarded as statistically significant.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| women with polycystic ovary syndrome | Active Comparator | 36 patients with PCOS |
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| Healthy women of reproductive age | Active Comparator | 30 patients with regular normal menstrual cycle |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| C type natriuretic peptide | Diagnostic Test | Serum level of CNP in PCOS and healthy women |
|
| Measure | Description | Time Frame |
|---|---|---|
| Serum CNP Levels of PCOS and Healthy Participants | The comparison of serum levels of C type natriuretic peptide among PCOS and healthy women | Second or Third Day of Menstruation |
| Roc Curve of CNP | We made a cut off value estimation for the diagnosis of PCOS by serum CNP levels using Receiver operator characteristics. The ROC curve incorporates both sensitivity (true positive rate) and specificity (true negative rate) providing a single assessment incorporating both measures. The higher the total area under the curve, the greater the predictive power of the CNP for diagnosing PCOS | Second or Third Day of Menstruation |
| Measure | Description | Time Frame |
|---|---|---|
| Comparison of FSH and LH of PCOS and Healthy Women | Serum FSH and LH of PCOS and healthy women were compared | Second or Third Day of Menstruation |
| Serum Estradiol Levels of PCOS and Healthy Women |
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Inclusion Criteria:
Exclusion Criteria:
women
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| Name | Affiliation | Role |
|---|---|---|
| Özay | Near East University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Near East University Faculty of Medicine | Nicosia | 99138 | Cyprus |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 20947764 | Background | Zhang M, Su YQ, Sugiura K, Xia G, Eppig JJ. Granulosa cell ligand NPPC and its receptor NPR2 maintain meiotic arrest in mouse oocytes. Science. 2010 Oct 15;330(6002):366-9. doi: 10.1126/science.1193573. | |
| 19429786 | Background | Norris RP, Ratzan WJ, Freudzon M, Mehlmann LM, Krall J, Movsesian MA, Wang H, Ke H, Nikolaev VO, Jaffe LA. Cyclic GMP from the surrounding somatic cells regulates cyclic AMP and meiosis in the mouse oocyte. Development. 2009 Jun;136(11):1869-78. doi: 10.1242/dev.035238. |
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For the last 6 months, patients with drug use that may affect menstruation like oral contraceptives, patients with cardiac or renal disease and therefore drug use, patients with hypertension hystory, history of ovarian surgery, current pregnancy, hyperprolactinemia, thyroid disease, congenital adrenal hyperplasia.
The patients were recruited from Near East University Hospital, Department of Obstetrics and Gynecology.
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| ID | Title | Description |
|---|---|---|
| FG000 | Women With Polycystic Ovary Syndrome | 36 patients with PCOS C type natriuretic peptide: Serum level of CNP in PCOS and healthy women |
| FG001 | Healthy Women of Reproductive Age |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jul 1, 2021 |
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Serum Estradiol levels of PCOS and Healthy Women were compared
| Second or Third Day of Menstruation |
| Serum Tiroid Stimulating Hormone of PCOS and Healthy Women | serum tiroid stimulating hormone of PCOS and healthy women were compared | Second or Third Day of Menstruation |
| Serum Prolactin Levels of PCOS and Healthy Women | serum prolactin levels of PCOS and healthy women were compared | Second or Third Day of Menstruation |
| Serum Androstenedione Levels of PCOS and Healthy Women | Serum Androstenedione Levels of PCOS and Healthy Women were compared | Second or Third Day of Menstruation |
| Serum Dehydroepiandrosterone Sulfate (DHEAS) Levels of PCOS and Healthy Women | Serum dehydroepiandrosterone sulfate (DHEAS) Levels of PCOS and Healthy Women were compared | Second or Third Day of Menstruation |
| Serum Total Testosterone Levels of PCOS and Healthy Women | Serum Total Testosterone Levels of PCOS and Healthy Women were compared | Second or Third Day of Menstruation |
| Serum Free Testosterone Levels of PCOS and Healthy Women | Serum Free Testosterone Levels of PCOS and Healthy Women were compared | Second or Third Day of Menstruation |
| Serum Sex Hormone Binding Globulin Levels of PCOS and Healthy Women | Serum Sex Hormone Binding Globulin Levels of PCOS and Healthy Women were compared | Second or Third Day of Menstruation |
| Free Androgen Index of Participants | Free androgen index of participants were compared. It was calculated with the formula 100XTotal testosterone/Sex hormone binding globulin | Second or Third Day of Menstruation |
| Serum Glucose, Total Cholesterol and Triglycerides Levels of Participants | Serum glucose, total cholesterol and triglycerides levels of participants were compared | Second or third day of menstruation and morning fasting |
| High Density Lipoprotein and Low Density Lipoprotein Levels of Participants | High density lipoprotein and low density lipoprotein levels of participants were compared | Second or Third Day of Menstruation-morning fasting |
| Serum Insulin Levels of Participants | Serum Insulin Levels of Participants were compared | Second or Third Day of Menstruation-morning fasting |
| Homeostatic Model Assessment of Insulin Resistance of Participants | homeostatic model assessment of insulin resistance of participants were compared. The calculation was made with formula Glucose X Insulin/405. | Second or Third Day of Menstruation-morning fasting |
| 19474061 | Background | Vaccari S, Weeks JL 2nd, Hsieh M, Menniti FS, Conti M. Cyclic GMP signaling is involved in the luteinizing hormone-dependent meiotic maturation of mouse oocytes. Biol Reprod. 2009 Sep;81(3):595-604. doi: 10.1095/biolreprod.109.077768. Epub 2009 May 27. |
| 8812137 | Background | Tsafriri A, Chun SY, Zhang R, Hsueh AJ, Conti M. Oocyte maturation involves compartmentalization and opposing changes of cAMP levels in follicular somatic and germ cells: studies using selective phosphodiesterase inhibitors. Dev Biol. 1996 Sep 15;178(2):393-402. doi: 10.1006/dbio.1996.0226. |
| 11944932 | Background | Thomas RE, Armstrong DT, Gilchrist RB. Differential effects of specific phosphodiesterase isoenzyme inhibitors on bovine oocyte meiotic maturation. Dev Biol. 2002 Apr 15;244(2):215-25. doi: 10.1006/dbio.2002.0609. |
| 12773402 | Background | Nogueira D, Albano C, Adriaenssens T, Cortvrindt R, Bourgain C, Devroey P, Smitz J. Human oocytes reversibly arrested in prophase I by phosphodiesterase type 3 inhibitor in vitro. Biol Reprod. 2003 Sep;69(3):1042-52. doi: 10.1095/biolreprod.103.015982. Epub 2003 May 28. |
| 23255339 | Background | Lee KB, Zhang M, Sugiura K, Wigglesworth K, Uliasz T, Jaffe LA, Eppig JJ. Hormonal coordination of natriuretic peptide type C and natriuretic peptide receptor 3 expression in mouse granulosa cells. Biol Reprod. 2013 Feb 21;88(2):42. doi: 10.1095/biolreprod.112.104810. Print 2013 Feb. |
| 23331536 | Background | Hiradate Y, Hoshino Y, Tanemura K, Sato E. C-type natriuretic peptide inhibits porcine oocyte meiotic resumption. Zygote. 2014 Aug;22(3):372-7. doi: 10.1017/S0967199412000615. Epub 2013 Jan 18. |
| 21865234 | Background | Kawamura K, Cheng Y, Kawamura N, Takae S, Okada A, Kawagoe Y, Mulders S, Terada Y, Hsueh AJ. Pre-ovulatory LH/hCG surge decreases C-type natriuretic peptide secretion by ovarian granulosa cells to promote meiotic resumption of pre-ovulatory oocytes. Hum Reprod. 2011 Nov;26(11):3094-101. doi: 10.1093/humrep/der282. Epub 2011 Aug 23. |
| 29535265 | Background | Wang X, Wang H, Liu W, Zhang Z, Zhang Y, Zhang W, Chen Z, Xia G, Wang C. High level of C-type natriuretic peptide induced by hyperandrogen-mediated anovulation in polycystic ovary syndrome mice. Clin Sci (Lond). 2018 Apr 6;132(7):759-776. doi: 10.1042/CS20171394. Print 2018 Apr 16. |
| 29739821 | Background | Reis AM, Honorato-Sampaio K. C-type natriuretic peptide: a link between hyperandrogenism and anovulation in a mouse model of polycystic ovary syndrome. Clin Sci (Lond). 2018 May 8;132(9):905-908. doi: 10.1042/CS20171491. Print 2018 May 16. |
| 14711538 | Background | Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril. 2004 Jan;81(1):19-25. doi: 10.1016/j.fertnstert.2003.10.004. |
| 36373234 | Derived | Ozay AC, Ozay OE, Edebal OH. Role of C-type natriuretic peptide in polycystic ovary syndrome. Int J Gynaecol Obstet. 2023 May;161(2):601-606. doi: 10.1002/ijgo.14568. Epub 2022 Nov 25. |
30 patients with regular normal menstrual cycle
C type natriuretic peptide: Serum level of CNP in PCOS and healthy women
| COMPLETED |
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| NOT COMPLETED |
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36 PCOS patient according to Rotterdam criterias and 30 healthy control women
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| ID | Title | Description |
|---|---|---|
| BG000 | Women With Polycystic Ovary Syndrome | 36 patients with PCOS C type natriuretic peptide: Serum level of CNP in PCOS and healthy women |
| BG001 | Healthy Women of Reproductive Age | 30 patients with regular normal menstrual cycle C type natriuretic peptide: Serum level of CNP in PCOS and healthy women |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants | Participants |
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| Age, Continuous | Median | Inter-Quartile Range | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Race/Ethnicity, Customized | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| Body Mass Index | Mean | Standard Deviation | kg/m^2 |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Serum CNP Levels of PCOS and Healthy Participants | The comparison of serum levels of C type natriuretic peptide among PCOS and healthy women | Posted | Median | Inter-Quartile Range | pg/ml | Second or Third Day of Menstruation |
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| Primary | Roc Curve of CNP | We made a cut off value estimation for the diagnosis of PCOS by serum CNP levels using Receiver operator characteristics. The ROC curve incorporates both sensitivity (true positive rate) and specificity (true negative rate) providing a single assessment incorporating both measures. The higher the total area under the curve, the greater the predictive power of the CNP for diagnosing PCOS | Posted | Number | 95% Confidence Interval | probability | Second or Third Day of Menstruation |
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| Secondary | Comparison of FSH and LH of PCOS and Healthy Women | Serum FSH and LH of PCOS and healthy women were compared | FSH and LH should be evaluated during menstruation time period ( day 3) | Posted | Median | Inter-Quartile Range | mIU/mL | Second or Third Day of Menstruation |
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| Secondary | Serum Estradiol Levels of PCOS and Healthy Women | Serum Estradiol levels of PCOS and Healthy Women were compared | Posted | Median | Inter-Quartile Range | pg/mL | Second or Third Day of Menstruation |
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| Secondary | Serum Tiroid Stimulating Hormone of PCOS and Healthy Women | serum tiroid stimulating hormone of PCOS and healthy women were compared | Posted | Median | Inter-Quartile Range | mIU/L | Second or Third Day of Menstruation |
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| Secondary | Serum Prolactin Levels of PCOS and Healthy Women | serum prolactin levels of PCOS and healthy women were compared | Posted | Mean | Standard Deviation | ng/mL | Second or Third Day of Menstruation |
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| Secondary | Serum Androstenedione Levels of PCOS and Healthy Women | Serum Androstenedione Levels of PCOS and Healthy Women were compared | Posted | Mean | Standard Deviation | ng/dL | Second or Third Day of Menstruation |
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| Secondary | Serum Dehydroepiandrosterone Sulfate (DHEAS) Levels of PCOS and Healthy Women | Serum dehydroepiandrosterone sulfate (DHEAS) Levels of PCOS and Healthy Women were compared | Posted | Median | Inter-Quartile Range | µg/dL | Second or Third Day of Menstruation |
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| Secondary | Serum Total Testosterone Levels of PCOS and Healthy Women | Serum Total Testosterone Levels of PCOS and Healthy Women were compared | Posted | Mean | Standard Deviation | nmol/L | Second or Third Day of Menstruation |
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| Secondary | Serum Free Testosterone Levels of PCOS and Healthy Women | Serum Free Testosterone Levels of PCOS and Healthy Women were compared | Posted | Mean | Standard Deviation | pg/mL | Second or Third Day of Menstruation |
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| Secondary | Serum Sex Hormone Binding Globulin Levels of PCOS and Healthy Women | Serum Sex Hormone Binding Globulin Levels of PCOS and Healthy Women were compared | Posted | Median | Inter-Quartile Range | nmol/L | Second or Third Day of Menstruation |
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| Secondary | Free Androgen Index of Participants | Free androgen index of participants were compared. It was calculated with the formula 100XTotal testosterone/Sex hormone binding globulin | Posted | Mean | Standard Deviation | % of T testosterone per SHBG | Second or Third Day of Menstruation |
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| Secondary | Serum Glucose, Total Cholesterol and Triglycerides Levels of Participants | Serum glucose, total cholesterol and triglycerides levels of participants were compared | Posted | Median | Inter-Quartile Range | mg/dL | Second or third day of menstruation and morning fasting |
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| Secondary | High Density Lipoprotein and Low Density Lipoprotein Levels of Participants | High density lipoprotein and low density lipoprotein levels of participants were compared | Posted | Mean | Standard Deviation | mg/dL | Second or Third Day of Menstruation-morning fasting |
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| Secondary | Serum Insulin Levels of Participants | Serum Insulin Levels of Participants were compared | Posted | Median | Inter-Quartile Range | mU/L | Second or Third Day of Menstruation-morning fasting |
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| Secondary | Homeostatic Model Assessment of Insulin Resistance of Participants | homeostatic model assessment of insulin resistance of participants were compared. The calculation was made with formula Glucose X Insulin/405. | Posted | Median | Inter-Quartile Range | HOMA-IR Index | Second or Third Day of Menstruation-morning fasting |
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Adverse events were not assessed.
Adverse events were not assessed.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Women With Polycystic Ovary Syndrome | 36 patients with PCOS C type natriuretic peptide: Serum level of CNP in PCOS and healthy women | 0 | 0 | 0 | 0 | 0 | 0 |
| EG001 | Healthy Women of Reproductive Age | 30 patients with regular normal menstrual cycle C type natriuretic peptide: Serum level of CNP in PCOS and healthy women | 0 | 0 | 0 | 0 | 0 | 0 |
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The limitation of our study was the relatively small number of participants.
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr.Ali Cenk Ozay | Near East University | 00905428583248 | dr.alicenk@hotmail.com |
| Oct 7, 2021 |
| Prot_SAP_000.pdf |
| ID | Term |
|---|---|
| D011085 | Polycystic Ovary Syndrome |
| D008599 | Menstruation Disturbances |
| D017588 | Hyperandrogenism |
| ID | Term |
|---|---|
| D010048 | Ovarian Cysts |
| D003560 | Cysts |
| D009369 | Neoplasms |
| D010049 | Ovarian Diseases |
| D000291 | Adnexal Diseases |
| D005831 | Genital Diseases, Female |
| D052776 | Female Urogenital Diseases |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
| D000091662 | Genital Diseases |
| D006058 | Gonadal Disorders |
| D004700 | Endocrine System Diseases |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D058489 | 46, XX Disorders of Sex Development |
| D012734 | Disorders of Sex Development |
| D014564 | Urogenital Abnormalities |
| D047808 | Adrenogenital Syndrome |
| D052801 | Male Urogenital Diseases |
| D000013 | Congenital Abnormalities |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
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| >=65 years |
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| Male |
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