Pretreatment with Transdermal Testosterone may Enhance Ovarian Response to FSH

The synergistic effects of androgens and follicle stimulating hormone (FSH) on folliculogenesis, a process critical for assisted reproduction techniques, have been previously established in primates. Now, a recent randomized clinical trial published in the journal Human Reproduction demonstrates that pretreatment with transdermal testosterone enhances the follicular response in poor IVF responders compared to the high-dose gonadotropin and minidose GnRH agonist protocol.
Francisco Jose Fabregues Gasol, from the Institut Clínic of Gynecology, Obstetrics and Neonatology, University of Barcelona, Spain, and colleagues, conducted a randomized trial to explore the efficacy of transdermal testosterone pretreatment in poor IVF responders. Sixty-two infertile women with a history of poor follicular response to IVF cycle were equally divided into two groups for their second IVF treatment. The first group received transdermal testosterone prior to standard ovarian stimulation, along with gonadotropin under pituitary suppression. On the other hand, the second group was administered with high-dose gonadotropin, along with a low-dose gonadotropin releasing hormone (GnRH) agonist protocol for ovarian stimulation.
Investigators observed that the first group had 32.2% cycles with low response, as compared to 71% in the other group. Also, ovum retrieval was more in the first group of patients (80.6%) in contrast to the second group (58.1%), with statistically significant difference (81.2% vs. 41.1%) in patients with normal basal FSH levels. The study results showed that the ovarian sensitivity to FSH and the response of follicles to gonadotropin treatment could be enhanced through transdermal testosterone pretreatment in poor IVF responders.
Earlier, Balasch and colleagues (Human Reproduction, 2006) conducted a self-controlled, therapeutic clinical trial on 25 infertile women with a history of poor follicular response, leading to cancellation of first and second IVF cycles. It was observed that pretreatment with transdermal testosterone could be an effective approach for poor IVF responders with normal basal FSH concentration but poor controlled ovarian stimulation response.
In a contradictory study, Massin, et al. (Human Reproduction, 2006) observed that testosterone administration does not significantly affect the ovarian response to FSH. The researchers conducted a double-blind study on women with a background of low response to controlled ovarian stimulation and a low hormonal ovarian reserve, to evaluate the effects of androgen application. The subjects were randomized to receive either transdermal testosterone or placebo gel for 15 days prior to gonadotropin administration for a second IVF cycle. Both cycles involved identical GnRH analogue and equal FSH daily doses. Plasma testosterone levels were substantially enhanced, with no similar effects on the antral follicular count in the test group. There was no significant difference in both the groups with regard to the main ovarian response parameters such as pre-ovulatory follicular number, and the count of total and mature oocytes and embryos. Based on their findings the investigators emphasized on further clinical trials to study the effects of optimal dose and duration for testosterone administration.
Conditions, such as high body mass index, pelvic adhesions, prior ovarian surgery, or progressive age, could be related with low ovarian response to gonadotropin treatment. The outcome of an IVF treatment is directly dependent on the number of embryos available. Poor ovarian response could lead to low embryo count, resulting in decreased pregnancy rates. Kailasam and colleagues (Human Reproduction, 2004) defined poor response in women aged <40 years, as cancellation of the cycle in patients on ≥300 IU FSH/day, (<3 pre-ovulatory follicle development), or the requirement for the total administration of ≥3000 IU FSH for sufficient follicular recruitment, substantiating oocyte retrieval.
Poor ovarian response to standard FSH treatment is a major concern in assisted reproduction processes. The current study, which demonstrates the enhanced ovarian sensitivity to gonadotropin in poor IVF responders, by pretreatment with transdermal testosterone, could serve as a novel approach to achieve enhanced success of IVF treatment.
References
1. Fábregues F, Peñarrubia J, Creus M, et al. Transdermal testosterone may improve ovarian response to gonadotrophins in low-responder IVF patients: a randomized, clinical trial. Hum Reprod. 2008 Dec 3. [Epub ahead of print]
2. Balasch J, Fábregues F, Peñarrubia J, et al. Pretreatment with transdermal testosterone may improve ovarian response to gonadotrophins in poor-responder IVF patients with normal basal concentrations of FSH. Hum Reprod. 2006 Jul;21(7):1884-93.
3. Massin N, Cedrin-Durnerin I, Coussieu C, Galey-Fontaine J, Wolf JP, Hugues JN. Effects of transdermal testosterone application on the ovarian response to FSH in poor responders undergoing assisted reproduction technique–a prospective, randomized, double-blind study. Hum Reprod. 2006 May;21(5):1204-11.
4. Kailasam C, Keay SD, Wilson P, Ford WC, Jenkins JM. Defining poor ovarian response during IVF cycles, in women aged <40 years, and its relationship with treatment outcome. Hum Reprod. 2004 Jul;19(7):1544-7.

Cryptorchidism May be Associated with Genetic Mutations

Cryptorchidism, a common congenital defect of the male genitalia that affects 3-4% of full-term infants and 30% of those born prematurely, poses a risk for infertility and testicular cancer. However, the exact etiology and pathogenesis of cryptorchidism are not clearly known. Now, a recent study published in the Journal of the American Medical Association has identified a potential link between cryptorchidism and genetic alterations such as insulin-like factor 3 (INSL3) receptor gene mutations and Klinefelter syndrome.
Alberto Ferlin from the Department of Histology, Microbiology, and Medical Biotechnologies, University of Padova, Italy, and coworkers, conducted the case-control study on 600 male infants in Italy during 2003 to 2005, to investigate the rate of genetic alterations in cryptorchidism. Three hundred noncryptorchid boys between 1 to 4 years were selected as controls. Follow-up of the subjects was done for 2 to 3 years and those with persistent cryptorchidism were treated with orchidopexy.
Study results showed that mutations ranged from low in boys with cryptorchidism (2.8%), to high in those with persistent cryptorchidism (5.3%) and bilateral cryptorchidism (8.3%), compared to controls (0.3%). The calculated odds for having genetic alteration in boys with persistent cryptorchidism were more than 17 times; however, there was lack of mutations in boys with low gestational age or low birth weight and those who had spontaneous descent of the testes. The researchers found that Klinefelter syndrome and INSL3 receptor gene mutations were most frequently associated with cryptorchidism, suggesting a significant relationship between the disease and genetic alterations.
Early studies have indicated that INSL3 plays a key role in testicular descent, with mutations in the gene or its G protein-coupled receptor (leucine-rich repeat, containing G protein-coupled receptor (LGR8)) likely to be associated with cryptorchidism.
Ferlin, et al. (Molecular Human Reproduction, 2006) conducted a study to investigate the hypothesis pertaining to the relationship between INSL3 mutations and the signs of testicular dysgenesis syndrome (TDS), characterized by undescended testis, poor semen quality, testis cancer, and hypospadias. The analysis was performed on 967 subjects with maldescended testes and/or infertility and/or testicular cancer and 450 controls. The researchers also conducted in vitro functional analysis of genetic alterations (R4H, W69R, and R72K) by observing the increase of INSL3-dependent cAMP (cyclic adenosine monophosphate) in cells that express LGR8. It was found that 1.9% of the subjects had 6 INSL3 mutations, with no similar finding in the controls. Based on the findings, it was suggested that a significant link may exist between INSL3 gene alterations and TDS syndrome signs; although, a definite causative role was not established.
Although cryptorchidism or undescended testicle may occur bilaterally, it commonly affects the right testes. A combination of factors such as maternal health, genetics, and environment may play an important role in its development, but the exact cause is unknown. Generally, the condition resolves by itself but sometimes may require orchidopexy to relocate the testis into the scrotum.
Substantiating the current research, which identifies the association between undescended testicles and genetic mutations in INSL3 receptor gene and Klinefelter syndrome, with further larger studies, may help to elucidate the underlying disease mechanism. Further, this may facilitate in developing novel therapeutic strategies for patients with persistent and bilateral cryptorchidism, thereby reducing the burden associated with male infertility.
References
1. Ferlin A, Zuccarello D, Zuccarello B, Chirico MR, Zanon GF, Foresta C. Genetic alterations associated with cryptorchidism. JAMA. 2008 Nov 19;300(19):2271-6.
2. Ferlin A, Bogatcheva NV, Gianesello L, et al. Insulin-like factor 3 gene mutations in testicular dysgenesis syndrome: clinical and functional characterization. Mol Hum Reprod. 2006 Jun;12(6):401-6. Epub 2006 May 10.

How To Make Twins

Sunday Tricks

Weekend Drama

Welcome, Mr President

Lay Offs