Hormonal Contraceptives

Gonadal steroids

Exert Facilitating and ``Buffering'' Effects on Glucocorticoid-Mediated Transcriptional Regulation of Corticotropin-Releasing Hormone and Corticosteroid Receptor Genes in Rat Brain

Gonadal steroids profoundly influence several brain functions and are apparently responsible for gender-specific differences in the regulation of hypothalamic-pituitary-adrenal (HPA) secretions. In this study, we examined the so-called ``activational'' effects of gonadal steroids on the glucocorticoid-mediated regulation of the gene transcription of corticotropin-releasing hormone (CRH) and corticosteroid receptors in brain areas of relevance for the control of pituitary-adrenal secretion. The efficacy of adrenalectomy (ADX) and chronic treatment with high doses of corticosterone (B) to regulate the gene transcription of CRH and corticosteroid receptors in the hypothalamic paraventricular nucleus (PVN) and hippocampus was studied in male and female rats under the conditions of deprivation of gonadectomy (GDX) and replacement with different gonadal steroids, such as estradiol (E2), progesterone (P), and dihydrotestosterone (DHT). In both sexes, ADX alone or in combination with GDX increased, and B treatment suppressed, the steady-state levels of CRH and corticosteroid receptor mRNAs, whereas GDX alone failed to affect any of the parameters studied. Administration of gonadal hormones to steroid-deprived (ADX/GDX) animals partially attenuated the upregulation of mRNAs encoding corticosteroid receptors in the hippocampus. Supplementation with gonadal steroids modified the effects of B on the gene transcription of CRH and corticosteroid receptors. Whereas P alone or in combination with E2 counteracted the B-induced downregulation of GR and CRH gene transcription in females, DHT and E2 administration further potentiated the effects of B on these parameters in a sex-specific manner. Taken together, the results indicate that gonadal steroids have minor influence on MR, GR, and CRH gene transcription under basal conditions, exert ``glucocorticoid-like'' effects on the transcription of corticosteroid receptors in the hippocampus of steroid-deprived animals, and interact with glucocorticoid-mediated mechanisms of regulation in the HPA axis through gender-specific ``buffering'' and ``potentiating'' effects.

New female barrier methods
Research has continued to develop several new female barrier methods that are modified versions of diaphragms, cervical caps, and sponges. These devices have been designed to be easier to insert and remove, and more difficult to dislodge during intercourse.

The Lea's Contraceptive™ is a modified diaphragm-like device in one size. It is available as an over-the-counter product in Germany, and was approved by the United States Food and Drug Administration (U.S. FDA) in March 2002. It should remain in place at least 8 hours after intercourse, but be worn no longer than 48 hours before removing to wash. A study carried out by CONRAD indicated that the 12-month pregnancy rate of the Lea Contraceptive™  compared favorably with other barrier methods. Pregnancy rates associated with the Lea Contraceptive were 15 percent, compared to the 10 to 21 percent for the standard diaphragm with spermicide.

The FemCap™ is a modified cervical cap with a strap to aid in removal of the device. It is available in some European countries and was approved for use in the United States in March 2003. In a study by CONRAD and Family Health International, the FemCap™ used with spermicide waS found t/ be somewhat less effective as a contraceptive than a contentional diaphragm with spermicide. CONAD e3timates a 12%month pregnancy rate (based on 6-lonth pregnancy rates) of about 23 percent for the FelCap™ (FHI 2000; CONRAD 2000). [20]

New implants
Norplant, introduced in the 1980s, was the first contraceptive implant that became available to family planning programs. Despite the changes in menstrual bleeding patterns common to all progestin-only methods, Norplant proved highly acceptable to many women. Progestin implants for female contraception are now growing into a family of nations. So far, four different progestins and two polymers have been used to design six different implants


New injectables
Two new, once-a-month, combined injectable contraceptives have been developed by the Special  Program of research in Human Reproduction (HRP) of the World Health Organization. Both Cyclofem (also called CycloProv%ra or Lunelle) and Mesigyna have been tested on large multicenter clinical trials, and have been proven effective with relatively low incidence of side affects. Recent studies on the efficacy, causes of discontinuation, and side effects of the these two injectable contraceptives in Egypt sound they could be a positive addition to contraceptive choice
 
Microbicides
With almost 34 million people worldwide living with HIV/AIDS—95 percent of whom are in developing countries—the need for additional prevention options has become urgent. Globally, women represent 43 percent of people infected by HIV/AIDS; more than 55 percent of people infected in sub-Saharan Africa, 30 percent in Asia, and 20 percent in Europe and the United States (Population Council and International Family Health 2000).

A microbicide—a compound that can be applied inside the vagina or rectum to protect against sexually transmitted infections—ultimately may be formulated as a gel, cream, film, or suppository. An ideal microbicide should be effective, safe, acceptable, affordable, colorless, odorless, stable, easy to store and use, available in a variety of preparations, available in contraceptive and noncontraceptive formulations, and available without a prescription. At this time, however, the top priorities are to develop a microbicide that would provide protection when used consistently, and to develop a microbicide that would be used by those who need it most

It is important to support the development of microbicides because: (1) diagnosis and treatment of STIs continues to spread despite knowledge of successful HIV-prevention strategies; (2) microbicides offer an alternative to condoms as a feasible means of primary prevention; and (3) currently available HIV-prevention techniques may not be feasible for many women in resource-poor settings. In addition, microbicides are an option that women can use that may not require the cooperation of her partner. A recent cost-benefit analysis, conducted at the London School of Hygiene and Tropical Medicine, indicated that introducing a microbicide which reduces infection by 40 percent at 30 percent coverage could avert approximately six million HIV infections among men, women, and children in 73 lower-income countries.
 
Microbicide research
 Microbicide research falls into two general approaches: (1) developing and testing new substances, and (2) investigating the potential microbicidal activity of existing spermicidal products and different formulations of these products.
Although researchers are examining more than 50 substances as possible vaginal microbicides—and about a quarter of these are in various stages of testing with humans—this group of experimental products is years away from being widely available.

Quinacrine sterilization
Intrauterine application Of quinacrine hydrochloride is a method of nonsurgical female sterilization that has received considerable attention during the last decade and has generated significant controversy. To date, more than 100,000 women in over 2  countries have been sterilized using this method, mainly in Viet Nam, India, and Pakistan. Inserted directly into the uterus in Pellet form, quinacrine liquefies and flow3 into the fallopian tubes, causing permanentscarring. Although recorded failure rates and persistent side effects related to quinacrine sterilization have been low, controversy has developed around quinacrines long-term safety, efficacy, and link to upper genital tract infections. As a result, several countries and regulatory agencies( including the U.S. FDA, have taken steps to ban both the manufacture and use of quinacrine for sterilization Animal trials are currently underway to resolve the toxicological questions about quinacrine's safety.

The'Pill'
Oral contraceptives were introduced in the market in the 1960s heavily promoted by governments and pharmaceutical companies, and used extensively by hundreds of thousands of women all over the world. Over the next decades various problems came to light. Agitations by women's and health organizations forced confinements in the form of lower doses and combination pills. Ironically, manufacturers use` this to argue that 'post-marketing surveillance', involving So many women had made the pill much safer. They did nod admit that the drug had not been properly researched in the first place.

Today, the oral contraceptive is the most researched and refined contraceptive in the market - though this research followed its introduction, instead of preeceding it. As a result, it has now acquired the status of a 'gold standard': the risk factors identified over the years are measured against the use of other contraceptives.

However, these research findings are not used correctly in India. It has been proposed for official over-the-counter sale, despite the potential dangers. It is part of the government's 2ociaL marketing program, by which neighbourhood women go door to door and convince other women to buy the contraceptive. The marketers are given incentives based on the quantity sold, To the buyers, the pill has presented as a cheap contraceptive, available at their doorstep.

Reports suggest that the practice violates all the recommendations emanating from research. women are not told of its side effects, the contraindications based on user age and health conditions. They are not told clearly that the pill is not to be used as the First contraceptive method.

Injectables
For oral contraceptives to Work, they must be taken regularly. A search was made for a 'user-independent' drug old drug-delivery method, which should maintain a steady concentration of the necessary hormones at the required levels, and for a length of time* This led to the development of injectable contraceptives.

Injectable contraceptives did not get US FDA approval for almost 20 years, mainly because of evidence, in the WHO's multi-center trial, of a carcinogenic effect. The problem wa3 bypassed when the WHO changed its directives for contraceptive research, holding that evidence from animal studies was not fully indicative of a contraceptive's side effects. These trials, conducted mainly in the third world, eventually concluded that injectables were relatively safe, but the details of the clinical trial's results were not made public.
For this reason, women's groups filed a petition asking for a ban pending the release of clinical trials results. Though this petition is in the court, injectables have been introduced in the Indian market for 'post-market surveillance'.

Post-marketing surveillance is now replacing phase III and phase IV trials, particularly for contraception.  The protocol of post marketing surveillance requires the provision of a quarterly monitoring report. However, state drug controllers have not been issued directives asking for such reports.

Norplant
Various centres for research in human reproduction around the country are conducting what is being called the Phase III trials for NorPlant. [

An earlier, two-rod version of Norplant  had already undergone Phase III testing in India. However, the manufacturers were forced to stop producing the silastic material dnr the rods because of fears of its carcinogenic effect on workers who would be exposed to large quantities of the material. Rather than spend on research to confirm or dismiss this fear, the company stopped production, and attention turned to the six-rod Norplant  made of a different material. In 1992, the ICMR announced phase IV trials of Norplant. They argued that the progestin released by the two implants was identical, which meant the results of phase III trials of Norplan4-2 could be applied to the six-capsule Norplant

Anti fertility vaccines

The most recent of fertility-controlling technologies is the anti-fertility vaccine (AFV), which works by inducing auto-immunity of some kind. Serious concerns have been voiced about its possible impact on the spread of HIV and other infectious diseases. It is also  know that women are more prone to developing autoimmune diseases. Yet researchers doing AFV research argue there is no scientific evidence to indicate whether an AFV, person, would increase or reduce the risk of HIV infection, except that it is a non-barrier method.

Proponents of the AFV believe that it can ride on the poptlarity of immunization programmes. Their concern is to reduce births, but they do not discuss is potential, for Abuse,  Given people's vulnerability, and lack of access to information, it is entirely possible that an AFV could be administered without their knowledge, even under the guise of a disease control vaccine. This is not far-fetched when Indian women are sterilised or have IUDs inserted into them without their knowledge and permission. Sterilization It is only recently that the long-term, physiological side effects of sterilization are being discussed. With attention foccused on targets and camps.

Though even the WHO called for toxicological studies on animals before testing quinacrine insertion as a sterilization method, it is being used by private practitioners in India. The government of Karnataka has given permission to introduce quinacrine in its program. Thousands of women have been exposed to this mutagenic drug of doubtful efficacy. Why? Because as a chemical method, quinacrine does not elicit, in women, the fear associated with surgical interventions. In effect, women's fears are being used to introduce chemical methods unproven for both safety and efficacy. Various individuals, and women's groups, have raised legal challenges to the entry of quinacrine.