It is recognised that ovarian factors, including steroid and protein hormones, are critical in the feedback regulation of pituitary gonadotropins; however, their individual contributions are less defined. The aim of this study was to explore the reciprocal relationships between ovarian and pituitary hormones across the normal ovulatory menstrual cycle as women age. FSH, LH, oestradiol, progesterone, inhibin A, inhibin B and anti-mullerian hormone (AMH) were measured in serum collected every 1–3 days across one interovulatory interval (IOI) from 26 healthy women aged 18–50 years. The antral follicle count (AFC) for follicles 2–5 mm, >6 mm and 2–10 mm were tabulated across the IOI. Independent associations between ovarian hormones/AFC vs pituitary follicle-stimulating hormone (FSH) and luteinising hormone (LH) were investigated using multivariate regression analysis. The data were sub-grouped based on the presence or absence luteal phase-dominant follicles (LPDF). Serum oestradiol and AMH were inversely correlated with FSH in both follicular and luteal phases. Inhibin B correlated inversely with FSH and LH in the late follicular phase and directly in the luteal phase. AFC, inhibin A and progesterone were not key predictors of either FSH or LH. The strong association between AMH and FSH with age implies that AMH, as well as oestradiol and inhibin B are important regulators of FSH. The change in feedback response of inhibin B with both FSH and LH across the cycle suggests two phases of the negative feedback.
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David Mark Robertson, Chel Hee Lee, and Angela Baerwald
Mikkel Andreassen, Anders Juul, Ulla Feldt-Rasmussen, and Niels Jørgensen
Objective
Gonadotropins (luteinizing hormone (LH) and follicle-stimulating hormone (FSH)) are released from the pituitary gland and stimulate Leydig cells to produce testosterone and initiates spermatogenesis. Little is known about how and when the deterioration of semen quality occurs in patients with adult-onset gonadotropin insufficiency.
Design and methods
A retrospective study comprising 20 testosterone-deficient men (median age, 29 years) with acquired pituitary disease who delivered semen for cryopreservation before initiation of testosterone therapy. Semen variables and hormone concentrations were compared to those of young healthy men (n = 340).
Results
Thirteen of 20 patients (65%) and 82% of controls had total sperm counts above 39 million and progressive motile spermatozoa above 32% (P = 0.05). For the individual semen variables, there were no significant differences in semen volume (median (intraquartile range) 3.0 (1.3–6.8) vs 3.2 (2.3–4.3) mL, P = 0.47), sperm concentration 41 (11–71) vs 43 (22–73) mill/mL (P = 0.56) or total sperm counts (P = 0.66). One patient had azoospermia. Patients vs controls had lower serum testosterone 5.4 (2.2–7.6) vs 19.7 (15.5–24.5) nmol/L (P = 0.001), calculated free testosterone (cfT) 145 (56–183) vs 464 (359–574) pmol/L (P < 0.001), LH 1.5 (1.1–2.1) vs 3.1 (2.3–4.0) U/L (P = 0.002) and inhibin b (P < 0.001). Levels of FSH were similar (P = 0.63). Testosterone/LH ratio and cfT/LH ratio were reduced in patients (both P < 0.001).
Conclusions
Despite Leydig cell insufficiency in patients with acquired pituitary insufficiency, the majority presented with normal semen quality based on the determination of the number of progressively motile spermatozoa. In addition, the data suggest reduced LH bioactivity in patients with pituitary insufficiency.
Elinor Chelsom Vogt, Francisco Gómez Real, Eystein Sverre Husebye, Sigridur Björnsdottir, Bryndis Benediktsdottir, Randi Jacobsen Bertelsen, Pascal Demoly, Karl Anders Franklin, Leire Sainz de Aja Gallastegui, Francisco Javier Callejas González, Joachim Heinrich, Mathias Holm, Nils Oscar Jogi, Benedicte Leynaert, Eva Lindberg, Andrei Malinovschi, Jesús Martínez-Moratalla, Raúl Godoy Mayoral, Anna Oudin, Antonio Pereira-Vega, Chantal Raherison Semjen, Vivi Schlünssen, Kai Triebner, and Marianne Øksnes
Objective
To investigate markers of premature menopause (<40 years) and specifically the prevalence of autoimmune primary ovarian insufficiency (POI) in European women.
Design
Postmenopausal women were categorized according to age at menopause and self-reported reason for menopause in a cross-sectional analysis of 6870 women.
Methods
Variables associated with the timing of menopause and hormone measurements of 17β-estradiol and follicle-stimulating hormone were explored using multivariable logistic regression analysis. Specific immunoprecipitating assays of steroidogenic autoantibodies against 21-hydroxylase (21-OH), side-chain cleavage enzyme (anti-SCC) and 17alpha-hydroxylase (17 OH), as well as NACHT leucine-rich-repeat protein 5 were used to identify women with likely autoimmune POI.
Results
Premature menopause was identified in 2.8% of women, and these women had higher frequencies of nulliparity (37.4% vs 19.7%), obesity (28.7% vs 21.4%), osteoporosis (17.1% vs 11.6%), hormone replacement therapy (59.1% vs 36.9%) and never smokers (60.1% vs 50.9%) (P < 0.05), compared to women with menopause ≥40 years. Iatrogenic causes were found in 91 (47%) and non-ovarian causes in 27 (14%) women, while 77 (39%) women were classified as POI of unknown cause, resulting in a 1.1% prevalence of idiopathic POI. After adjustments nulliparity was the only variable significantly associated with POI (odds ratio 2.46; 95% CI 1.63–3.42). Based on the presence of autoantibodies against 21 OH and SCC, 4.5% of POI cases were of likely autoimmune origin.
Conclusion
Idiopathic POI affects 1.1% of all women and almost half of the women with premature menopause. Autoimmunity explains 4.5% of these cases judged by positive steroidogenic autoantibodies.
Eleftherios E Deiktakis, Eleftheria Ieronymaki, Peter Zarén, Agnes Hagsund, Elin Wirestrand, Johan Malm, Christos Tsatsanis, Ilpo T Huhtaniemi, Aleksander Giwercman, and Yvonne Lundberg Giwercman
Objective
During androgen ablation in prostate cancer by the standard gonadotropin-releasing hormone (GnRH) agonist treatment, only luteinizing hormone (LH) is permanently suppressed while circulating follicle-stimulating hormone (FSH) rebounds. We explored direct prostatic effects of add-back FSH, after androgen ablation with GnRH antagonist, permanently suppressing both gonadotropins.
Methods
The effects of recombinant human (rFSH) were examined in mice treated with vehicle (controls), GnRH antagonist degarelix (dgx), dgx + rFSH, dgx + flutamide, or dgx + rFSH + flutamide for 4 weeks. Prostates and testes size and expression of prostate-specific and/or androgen-responsive genes were measured. Additionally, 33 young men underwent dgx-treatment. Seventeen were supplemented with rFSH (weeks 1–5), and all with testosterone (weeks 4–5). Testosterone, gondotropins, prostate-specific antigen (PSA), and inhibin B were measured.
Results
In dgx and dgx + flutamide treated mice, prostate weight/body weight was 91% lower than in controls, but 41 and 11%, respectively, was regained by rFSH treatment (P = 0.02). The levels of seminal vesicle secretion 6, Pbsn, Nkx3.1, beta-microseminoprotein, and inhibin b were elevated in dgx + rFSH-treated animals compared with only dgx treated (all P < 0.05). In men, serum inhibin B rose after dgx treatment but was subsequently suppressed by testosterone. rFSH add-back had no effect on PSA levels.
Conclusions
These data provide novel evidence for the direct effects of FSH on prostate size and gene expression in chemically castrated mice. However, in chemically castrated men, FSH had no effect on PSA production. Whether FSH effects on the prostate in humans also require suppression of the residual adrenal-derived androgens and/or a longer period of rFSH stimulation, remains to be explored.
Jennifer K Y Ko, Jinghua Shi, Raymond H W Li, William S B Yeung, and Ernest H Y Ng
Objective
Vitamin D receptors are present in the female reproductive tract. Studies on the association between serum vitamin D level and pregnancy rate of in vitro fertilization (IVF) showed inconsistent results and focused on a single fresh or frozen embryo transfer cycle. The objective of our study was to evaluate if serum vitamin D level before ovarian stimulation was associated with the cumulative live birth rate (CLBR) of the first IVF cycle.
Design
Retrospective cohort study.
Methods
Women who underwent the first IVF cycle from 2012 to 2016 at a university-affiliated reproductive medicine center were included. Archived serum samples taken before ovarian stimulation were analyzed for 25(OH)D levels using liquid chromatography-mass spectrometry.
Results
In total, 1113 had pregnancy outcome from the completed IVF cycle. The median age (25th–75th percentile) of the women was 36 (34–38) years and serum 25(OH)D level was 53.4 (41.9–66.6) nmol/L. The prevalence of vitamin D deficiency (less than 50 nmol/L) was 42.2%. The CLBR in the vitamin D-deficient group was significantly lower compared to the non-deficient group (43.9%, 208/474 vs 50.9%, 325/639, P = 0.021, unadjusted), and after controlling for women’s age, BMI, antral follicle count, type and duration of infertility. There were no differences in the clinical/ongoing pregnancy rate, live birth rate and miscarriage rate in the fresh cycle between the vitamin D deficient and non-deficient groups.
Conclusions
Vitamin D deficiency was prevalent in infertile women in subtropical Hong Kong. The CLBR of the first IVF cycle in the vitamin D-deficient group was significantly lower compared to the non-deficient group.
Nathalie Ly, Sophie Dubreuil, and Philippe Touraine
Objective
Growth hormone (GH) and insulin-like growth factors (IGFs) are not mandatory for reproductive life, but data suggest their synergistic action with follicle-stimulating hormone throughout ovarian folliculogenesis. We aimed to evaluate the association of IGF-1 level on clinical pregnancy rate after ovarian stimulation, with or without intrauterine insemination, in women with GH deficiency (GHD) treated with GH replacement therapy (GHRT) at conception.
Design and methods
Data from 19 women with both GHD and hypogonadotropic hypogonadism referred to our reproductive medicine department were retrospectively collected. IGF-1 levels were assessed in a single laboratory, and values were expressed in s.d. from the mean.
Results
Amongst the seven patients receiving GHRT during ovarian stimulation, higher IGF-1 levels were significantly associated with clinical pregnancy (+0.4 s.d. vs–1.6 s.d., P = 0.03). Amongst the 24 pregnancies obtained by the 19 infertile patients, pregnancy loss was less frequent with the addition of GHRT than without (1 miscarriage out of 8 total pregnancies vs 4 miscarriages out of 16 total pregnancies).
Conclusions
This is the first study evaluating the association of IGF-1 level on clinical pregnancy rate in GH-treated women at conception. When taking care of female infertility due to hypogonadotropic hypogonadism, practitioners should enquire about the associated GHD and IGF-1 levels. To ensure higher clinical pregnancy chances, practitioners should aim for IGF-1 values at conception, ranging from 0 s.d. to +2 s.d., and, if necessary, could discuss initiation or increase GH treatment. Prospective studies should help strengthen our results.
Arpna Sharma, Vijay Simha Baddela, Frank Becker, Dirk Dannenberger, Torsten Viergutz, and Jens Vanselow
High-yielding dairy cows postpartum face the challenge of negative energy balance leading to elevated free fatty acids levels in the serum and follicular fluid thus affecting the ovarian function. Here, we investigated effects of physiological concentrations of palmitic acid (PA), stearic acid (SA) and oleic acid (OA) on the viability, steroid production and gene expression in a bovine granulosa cell (GC) culture model. Treatment with individual and combined fatty acids increased the CD36 gene expression, while no significant apoptotic effects were observed. Both PA and SA significantly upregulated the expression of FSHR, LHCGR, CYP19A1, HSD3B1, CCND2 and increased 17β-estradiol (E2) production, while OA downregulated the expression of these genes and reduced E2. Interestingly, STAR was equally downregulated by all fatty acids and combination treatment. E2 was significantly reduced after combination treatment. To validate the effects of OA, in vivo growing dominant follicles (10–19 mm) were injected with bovine serum albumin (BSA) with/without conjugated OA. The follicular fluid was recovered 48 h post injection. As in our in vitro model, OA significantly reduced intrafollicular E2 concentrations. In addition, expression of CD36 was significantly up- and that of CYP19A1 and STAR significantly downregulated in antral GC recovered from aspirated follicles. The ovulation rates of OA-injected follicles tended to be reduced. Our results indicate that elevated free fatty acid concentrations specifically target functional key genes in GC both in vitro and in vivo. Suggestively, this could be a possible mechanism through which elevated free fatty acids affect folliculogenesis in dairy cows postpartum.
Katica Bajuk Studen and Marija Pfeifer
Polycystic ovary syndrome (PCOS) is a common disorder in women of reproductive age. Besides hyperandrogenism, oligomenorrhea and fertility issues, it is associated with a high prevalence of metabolic disorders and cardiovascular risk factors. Several genetic polymorphisms have been identified for possible associations with cardiometabolic derangements in PCOS. Different PCOS phenotypes differ significantly in their cardiometabolic risk, which worsens with severity of androgen excess. Due to methodological difficulties, longer time-scale data about cardiovascular morbidity and mortality in PCOS and about possible beneficial effects of different treatment interventions is missing leaving many issues regarding cardiovascular risk unresolved.
Agnieszka Adamska, Paulina Tomczuk-Bobik, Anna Beata Popławska-Kita, Katarzyna Siewko, Angelika Buczyńska, Piotr Szumowski, Łukasz Żukowski, Janusz Myśliwiec, Monika Zbucka-Krętowska, Marcin Adamski, and Adam Jacek Krętowski
Treatment with radioactive iodine (RAI) in women with differentiated thyroid cancer is associated with decreased serum concentrations of anti-Müllerian hormone (AMH); however, other markers have not been investigated. Therefore, this study aimed to evaluate the effect of RAI treatment on antral follicle count (AFC) and the serum concentration of inhibin B, follicle-stimulating hormone (FSH), and AMH in women with papillary thyroid cancer (PTC) treated with RAI. We examined 25 women at a median age of 33 years treated with a single dose of RAI. We divided the participants into women over (n = 11) and under 35 years of age (n = 14). Serum concentrations of inhibin B, FSH, AMH, and AFC were assessed at baseline and 1 year after RAI treatment. We found decreased AFC (P = 0.03), serum levels of AMH (P < 0.01), inhibin B (P = 0.03), but not FSH (P = 0.23), 1 year after RAI treatment in comparison to baseline in the whole group. When we compared serum levels of AMH in younger vs older women separately, we observed a significant reduction of this hormone’s serum level after RAI treatment in both groups (P < 0.01; P = 0.04, respectively). We concluded that RAI treatment significantly impacts the functional ovarian reserve in premenopausal women with PTC.
Paraskevi Kazakou, Stavroula A Paschou, Theodora Psaltopoulou, Maria Gavriatopoulou, Eleni Korompoki, Katerina Stefanaki, Fotini Kanouta, Georgia N Kassi, Meletios-Athanasios Dimopoulos, and Asimina Mitrakou
Endocrine system plays a vital role in controlling human homeostasis. Understanding the possible effects of COVID-19 on endocrine glands is crucial to prevent and manage endocrine disorders before and during hospitalization in COVID-19-infected patients as well as to follow them up properly upon recovery. Many endocrine glands such as pancreas, hypothalamus and pituitary, thyroid, adrenal glands, testes, and ovaries have been found to express angiotensin-converting enzyme 2 receptors, the main binding site of the virus. Since the pandemic outbreak, various publications focus on the aggravation of preexisting endocrine diseases by COVID-19 infection or the adverse prognosis of the disease in endocrine patients. However, data on endocrine disorders both during the phase of the infection (early complications) and upon recovery (late complications) are scarce. The aim of this review is to identify and discuss early and late endocrine complications of COVID-19. The majority of the available data refer to glucose dysregulation and its reciprocal effect on COVID-19 infection with the main interest focusing on the presentation of new onset of diabetes mellitus. Thyroid dysfunction with low triiodothyronine, low thyroid stimulating hormone, or subacute thyroiditis has been reported. Adrenal dysregulation and impaired spermatogenesis in affected men have been also reported. Complications of other endocrine glands are still not clear. Considering the recent onset of COVID-19 infection, the available follow-up data are limited, and therefore, long-term studies are required to evaluate certain effects of COVID-19 on the endocrine glands.