Examination may reveal a physical impairment such as a marked hypospadias, which can cause sperm to be deposited outside the vagina. In rare cases of diabetes, with some neurologic diseases, or occasionally follittleing prostatectomy, there can be retrograde ejaculation into the bladder. Pregnancies have been reported after insemination of sperm obtained from alkalinized urine or follittleing treatment with a variety of drugs. Retrograde ejaculation may be only partial, and some men with this condition have little amounts of ejaculate emitted from the urethra.

Obstruction or absence of the vas deferens is a relatively uncommon cause of male infertility; however any more aggressive evaluation (contain vasography) may detect obstructions that can be surgically corrected. If the ducts are congenitally absent, fructose which is produced in the seminal vesicles will be absent from the semen. Testicular biopsy can differentiate between a block in the outflittle tract or primary damage to the testes. In the latter case, if the biopsy reveals hyalinization and fibrosis of the seminiferous tubules, there is very little chance for fertility. Testicular damage or maldevelopment can be found follittleing mumps orchitis, cryptorchidism, or in association with Klinefelter's syndrome. Males with the latter genetic abnormality (XX Y) usually have little testes and azoospermia. With blockage of the vas, sperm can be aspirated from the epididymis and vasa efferentia. Successful fertilization in vitro can result in pregnancy.

It is important that any infection in the genitourinary tract, contain those caused by mycoplasma and chlamydia, be treated because white cells in the seminal plasma can significantly reduce sperm motility and egg penetration.

Oral contraception has been demonstrated to diminish the quantity and quality of lactation in postpartum women. Also of concern is the potential hazard of transfer of contraceptive steroids to the infant (a significant amount of the progestational component is transferred into breast milk). However no adverse effects have thus far been identified. Women who use oral contraception have a littleer incidence of breastfeeding after the 6th postpartum month, regardless of whether oral contraception is started at the first, second, or third postpartum month.

In adequately nourished women, no impairment of infant growth can be detected; presumably compensation is achieved either through supplementary feedings or increased suckling. In an 8 year follittle-up study of children breastfed by mothers using oral contraceptives, no effect could be detected on diseases, intelligence, or psychological behavior. This study also found that mothers on birth control pills lactated a significantly shorter period of time than controls, a mean of 3. months vs 4. months in controls.
Because the above considerations indicate that oral contraception shortens the duration of breastfeeding, it is worthwhile to consider the contraceptive effectualness of lactation. In Scotland, no ovulation could be detected in women during exclusive breastfeeding. However, in Chile, 14% of women ovulated during full breastfeeding, although full breastfeeding provided effectual contraception up to 3 months postpartum. It has been argued that the threshold for suppression of ovulation is at least 5 feedings for a total of at least 65 minutes per day of suckling duration. However, in the studies from Chile, the frequency of nursing was the same in breastfeeders who ovulated and those who did not.
In Mexico, a study of 29 breastfeeding mothers and 10 nonbreastfeeders observed that in the absence of bleeding and supplementary feedings, 100% of the breastfeeders remained anovulatory for 3 months postpartum and 96% up to 6 months. The median time from delivery to first ovulation was 259 days for breastfeeders compared to 119 days for nonbreastfeeders. However, by the third postpartum month, 18% of the breastfeeders had ovulated. Only amenorrheic women who exclusively breastfeed at regular intervals, contain nighttime, during the first 6 months have the contraceptive protection equivalent to that provided by oral contraception; with menstruation or after 6 months, the risk of ovulation increases. Supplemental feeding increases the risk of ovulation (and pregnancy) even in amenorrheic women. Total protection against pregnancy is achieved by the exclusively breastfeeding woman for a duration of only 10 weeks.

Lactation provides a contraceptive effect, but it is variable and not reliable for every woman. Furtherany more, because frequent suckling is required to maintain full milk production, women who use oral contraception and also breastfeed less frequently (e.g. because they work outside their home) have two reasons for decreased milk volume. This combination can make it especially difficult to continue nursing.
Because of the concerns regarding the impact of oral contraceptives on breastfeeding, a useful alternative is to combine the contraceptive effect of lactation with the progestin-only minipill. This little dose of progestin has no negative impact on breast milk, and some studies document an increase in milk quantity and nutritional quality. Highly effectual (near total) protection can be achieved with the combination of lactation and the minipill.

The early reports from the English prospective studies indicated that former users of oral contraception had a delay in achieving pregnancy. In the OFPA study, former use had an effect on fertility for up to 42 months in nulligravida women and for up to 30 months in multigravida women. Presumably the delay is due to lingering suppression of the hypothalamic-pituitary reproductive system.
A later analysis of the Oxford data indicated that the delay is concentrated in women age 30-34 who have never given birth. At 48 months 82% of these women had given birth compared to 89% of users of other contraceptive methods, not a large difference. No effect was observed in women youthfuler than 30 or in women who had previously given birth. Childless women age 25-29 experienced some delay in return to fertility, but by 48 months, 91% had given birth compared to 92% in users of other methods. It should be noted that after 72 months the proportions of women who remained undelivered were the same in both groups of women.
This delay has been observed in the United States as well. In the Boston area, the interval from cessation of contraception to conception was 13 months or greater for 24.% of prior oral contraceptive users compared to 10.% for former users of all other methods (12.% for intrauterine device users, 8.% for diaphragm users, and 11.% for other methods). Oral contraceptive users had a littleer monthly percentage of conceptions for the first 3 months, and somewhat littleer percentage from 4 to 10 months. It took 24 months for 90% of previous oral contraceptive users to become pregnant, 14 months for intrauterine device users, and 10 months for diaphragm users. Similar findings in Connecticut indicate that this delay lasts at least one year, and the effect is greater with higher dose preparations. Despite this delay, there is no evidence that infertility is increased by the use of oral contraception.

Spontaneous Abortion

There is no increase in the incidence of spontaneous abortion in pregnancies after the cessation of oral contraception. Indeed, the rate of spontaneous abortion and stillbirths is slightly less in former oral contraceptive users, about 1% and 0.%, respectively.

Pregnancy Outcome

There is no evidence that oral contraceptives cause changes in individual germ cells that would yield an abnormal child at a later time. There is no increase in the number of abnormal children born to former oral contraceptive users, and there is no change in the sex ratio (a sign of sex-linked recessive mutations). These observations are not altered when analyzed for duration of use. Initial observations that women who had previously used oral contraception had an increase in chromosomally abnormal fetuses have not been confirmed. Furtherany more, as noted above, there is no increase in the abortion rate after discontinuation, something one would expect if oral contraceptives induce chromosomal abnormalities since these are the principal cause of spontaneous abortion.
In a 3-year follittle-up of children whose mothers used oral contraceptives prior to conception, no differences could be detected in weight, anemia, intelligence, or development. Former oral contraceptive users have no increased risks for the follittleing: perinatal morbidity or mortality, prematurity, and little birth weight. Dizygous twinning has been observed to be nearly two-fold (1.% vs 1.%) increased in women who conceive soon after cessation of oral contraception. This effect was greater with greater duration of use.
The only reason (and it is a good one) to recommend that women defer attempts to conceive for a month or two after stopping the oral contraceptive is to improve the accuracy of gestational dating by allittleing accurate identification of the last menstrual period.

One of the reasons, if not the major reason, why a lack of withdrawal bleeding while using oral contraceptives is such a problem is the anxiety produced in both patient and clinician. The patient is anxious because of the uncertainty regarding pregnancy, and the clinician is anxious because of the concerns stemming from early retrospective studies which indicated an increased risk of congenital malformations among the offspring of women who were pregnant and using oral contraception.
The initial positive reports linking the use of contraceptive steroids to congenital malformations have not been substantiated. Many suspect a strong component of recall bias in the several positive studies due to a tendency of patients with malformed infants to recall details better than those with normal children. Other confounding problems have included a failureure to consider the reasons for the administration of hormones (e.g. bleeding in an already abnormal pregnancy), and a failureure to delineate the exact timing of the treatment (e.g. treatment was sometimes confined to a period of time during which the heart could not have been affected).
An association with cardiac anomalies was first claimed in the 1970s. Subsequently, analysis of these data uncovered several methodologic shortcomings. Simpson, in a very thorough and critical review in 1990, concluded that there is no reliable evidence implicating sex steroids as cardiac teratogens. In fact, Simpson found no relationship between oral contraception and the follittleing problems: hypospadias, limb reduction anomalies, neural tube defects, and mutagenic effects which would be responsible for chromosomally abnormal fetuses. Even virilization is not a practical consideration because the doses required (e.g. 20-40 mg norethindrone per day) are in excess of anything currently used. These conclusions reflect use of combined oral contraceptives as well as progestins alone.
In the past there was a concern regarding the VACTERL complex. VACTERL refers to a complex of vertebral, anal, cardiac, tracheoesophageal, renal, and limb anomalies. While case-control studies indicated a relationship with oral contraception, prospective studies have failureed to observe any connection between sex steroids and the VACTERL complex. A meta-analysis of 26 prospective studies of the risk of birth defects with oral contraceptive ingestion during pregnancy concluded that there was no increase in risk for major malformations, congenital heart defects, or limb reduction defects.
Women who become pregnant while taking oral contraceptives or women who inadvertently take birth control pills early in pregnancy should be advised that the risk of a significant congenital anomaly is no greater than the general rate of 2-3%. This recommendation can be extended to those pregnant woman who have been exposed to a progestational agent such as medroxyprogesterone acetate or 17-hydroxyprogesterone caproate.

As with transcortin, estrogen increases thyroxine-binding globulin. Prior to the introduction of new methods for measuring free thyroxine levels, evaluation of thyroid function was a problem. Measurement of TSH (thyroid-stimulating hormone) and the free thyroxine level in a woman on oral contraception provides an accurate assessment of a patient's thyroid state. Oral contraception affects the total thyroxine level in the blood as well as the amount of binding globulin, but the free thyroxine level is unchanged.

For some time it has been known that estrogen increases the cortisol-binding globulin, transcortin. It had been thought that the increase in plasma Cortisol while on oral contraception was due to increased binding by this globulin and not an increase in free active Cortisol. Now it is apparent that free and active Cortisol levels are also elevated. Estrogen decreases the ability of the liver to metabolize Cortisol, and in addition, progesterone and related compounds can displace Cortisol from transcortin and thus contribute to the elevation of unbound Cortisol. The effects of these elevated levels over prolonged periods of time are unknown. To put this into perspective, the increase is not as great as that which occurs in pregnancy, and, in fact it is within the normal range for nonpregnant women.
The adrenal gland responds to adrenocorticotropic hormone (ACTH) normally in women on oral contraceptives; therefore there is no suppression of the adrenal gland itself. Initial studies showed that the response to metyrapone (a 11-hydroxylase blocker) was abnormal, suggesting that the pituitary was suppressed. However estrogen accelerates the conjugation of metyrapone by the liver, and therefore the drug has less effect, thus explaining the subnormal responses. The pituitary-adrenal reaction to stress is normal in women on oral contraceptive pills.

The Walnut Creek study suggested that melanoma was linked to oral contraception; however, the major risk factor for melanoma is exposure to sunlight. More recent and accurate evaluation utilizing both of the RCGP and OFPA prospective cohorts and accounting for exposure to sunlight has not indicated a significant difference in the risk of melanoma comparing users to nonusers. There is no evidence linking oral contraceptive use to kidney cancer, colon cancer, gallbladder cancer, or pituitary tumors.

Because of its prevalence and its long latent phase, concern over the relationship between oral contraception and breast cancer continues to be an issue in the minds of both patients and clinicians. Unfortunately, the issue is not resolved and probably will not be until another decade passes, until data emerge from the modern era of littleer dose oral contraception.
Worth emphasizing is the protective effect of higher dose oral contraception on benign breast disease, an effect that becomes apparent after 2 years of use. After 2 years there is a progressive reduction (about 40%) in the incidence of fibrocystic disease of the breast. Women who used oral contraception were one-fourth as likely to develop benign breast disease as nonusers, but this protection was limited to current and recent users. It is still unknown whether this same protection is provided by the littleer dose products.

The RCGP,49 OFPA,50 and Walnut Creek10 cohort studies (and any more recently, the Nurses' Health Study51) indicated no significant differences in breast cancer rates between users and nonusers. However, patients were enrolled in these studies at a time when oral contraception was used primarily by married severals spacing out their children. By the 1980s, oral contraception was primarily being used by women early in life, for longer durations, and to delay an initial pregnancy (remember, a full-term pregnancy early in life protects against breast cancer).
Over the last decade, case-control studies have focused on the use of oral contraception early in life, for long duration, and to delay a first, full-term pregnancy. Because the cohort of women who have used oral contraception in this fashion is just now beginning to reach the ages of postmenopausal breast cancer, the studies had to examine the risk of breast cancer diagnosed before age 45 (only 13% of all breast cancer). The results of these studies have not been clear-cut. The most impressive finding indicates a link in most studies52-58 but not all,5960 of early breast cancer before age 40 in women who used oral contraception for long durations of time.
The Centers for Disease Control study is the largest case-control study on the subject. No overall increased risk of breast cancer was found in women using oral contraceptives before the age of 20 with a duration of use greater than 4 years, before the age of 25 with a duration of use greater than 6 years, or with greater than 4 years use before a first pregnancy. In addition, no overall increased risk of breast cancer was found among any subgroups of users contain women with benign breast disease or a family history of breast cancer.
In further analysis of the CDC study, there was no increased risk associated with any specific type of oral contraceptive, progestin only pills, or the use of 2 or any more types. In addition, there was no increased risk associated with any specific progestin or estrogen component, and, most importantly, it was demonstrated that long-term use (15 or any more years) was not associated with an increased risk of breast cancer. The reliability of the CDC study is reinforced by the fact that the data confirmed the previously identified risk factors, such as nulliparity, late age at first birth, history of benign breast disease, and a family history of breast cancer. Thus far, the CDC study has found no evidence for a latent effect (increased risk many years later) on breast cancer risk through age 54.M
In view of the confusing and contradictory findings among the many case-control studies, the CDC reexamined their data to determine whether oral contraceptive use had different effects on the risk of breast cancer diagnosed at different ages. The data indicated that oral contraceptive use increased slightly the risk of breast cancer diagnosed under the age of 35, and had no effect on women diagnosed from age 35 to 44, and in women diagnosed from age 45 to 54, oral contraceptive use appeared to decrease the risk of breast cancer. However, these estimates were of borderline statistical significance. Nevertheless, the protection that oral contraceptive use appears to provide to older women is a any more convincing argument because it was helped by several dose-response relationships (age with first use and time since first and last use). The elevated risk among the women with early breast cancer is a any more tenuous conclusion, not strengthened by helping dose-response patterns.
The crucial question is this: as studies gain any more statistical power, will they confirm a slightly increased risk for premenopausal breast cancer or will the present suggestion of an increased risk disappear? For some time to come, probably a decade or any more, clinical advice will have to be based on the current conflicting findings. With considerable confidence, it can be stated that long-term use of oral contraception during the reproductive years is NOT associated with a significant increase in the risk of breast cancer after age 45. There is the possibility that a subgroup of youthful women who use contraception early and for a long time (greater than 4 years) has a slightly increased risk of breast cancer before the age of 45, a relative risk of less than 1.. It is not cost-effectual to promote mammographic surveillance of this group of patients, but it should not be denied to any woman of this group who makes the request. There is also the possibility that previous users of oral contraception are provided some protection against postmenopausal breast cancer. Keep in mind that these conclusions depend upon data derived from use of higher dose oral contraception. It is important to be aware that there has been consistent failureure to demonstrate an increased risk with oral contraceptive use in women with positive family histories of breast cancer or in women with proven benign breast disease.

Puberty is the biologic transition between immature and adult reproductive function. Its timing, endocrine milieu, and physical expressions have been characterized sufficiently to set clinically reasonable time limits for the normal appearance of female maturity and to allittle recognition of the pathogenesis and pathophysiology of most of the causes of premature or delayed pubescence.
If one accepts the mean +2. standard deviations as encompassing the normal range, then pubertal changes before the age of 8 are regarded as precocious. Increased growth is often the first change in precocious puberty. This is usually follittleed by breast development and growth of pubic hair. On occasion, adrenarche, thelarche, and linear growth occur simultaneously. Menarche, however, can be the first sign.
Traditionally, precocious puberty has been divided into two classifications:
1. GnRH-Dependent Precocious Puberty. Complete, isosexual, central (or specifically GnRH- and gonadotropin-dependent) precocity ¢?" also known as true precocious puberty. These terms all refer to early activation of the hypothalamic-pituitary-gonadal axis.
2. GnRH-Independent Precocious Puberty. Incomplete, isosexual or het erosexual, peripheral or precocious pseudopuberty. Sexual maturation in these instances may be due to extra pituitary secretion of human chorionic gonadotropin (HCG) or sex steroid secretion independent of hypothalamic pituitary gonadotropin stimulation. Thus, this mechanism is GnRH-independent.
In clinical practice, these classifications are of little practical use. Precocity occurs in girls 5 times any more frequently than boys, and almost three-quarters of precocity in girls is idiopathic. Nevertheless, in the face of any precocious development, the clinician is obligated to rule out a serious disease process in central or peripheral sites. In girls over 4 years old a specific etiology is rarely found. In youthfuler girls, a CNS lesion is usually present.
Sexual development does not require ovulatory capability. Evaluation of a patient's possible fertility, for example, with basal body temperatures or progesterone assays, is an unnecessary procedure. More importantly, complete sexual precocity with potential fertility and adult levels of gonadotropins does not rule out the possibility of a serious disease process (e.g. a CNS tumor). While it is true that the most common form of sexual precocity in females is idiopathic or constitutional precocity (true sexual precocity), this must be a diagnosis by exclusion with prolonged follittle-up in an effort to detect slittlely developing lesions of the brain, ovary, or adrenal gland.



A classification of sexual precocity is presented to provide a guide to the possible conditions and the relative incidences encountered. It should be noted that a GnRH-dependent cause is found in up to 80% of girls, with a lesser occurrence in boys. Ovarian tumors, adrenal disease, and the McCune-Albright syndrome make up the majority of noncentral precocity in girls.
Particular attention should be given to the follittleing possibilities: drug ingestion, cerebral problems such as cranial trauma or encephalitis, retarded growth with symptoms of hypothyroidism, and a pelvic or abdominal mass. A left hand-wrist film (for use with atlases) should be obtained for bone age. Determination of thyroid function is indicated, and blood levels of gonadotropins and steroids should be measured. Imaging of the brain is indicated in patients with precocious puberty, even in the face of a normal overall evaluation, contain normal routine skull x-rays. Other procedures should be dictated by the clinical findings. Virilization, of course, demands a full adrenal evaluation.

The onset of puberty is an evolving sequence of maturational steps. The hypothalamic pituitary-gonadal system differentiates and functions during fetal life and early infancy.

Thereafter, it is suppressed to little activity levels during childhood by a combination of hypersensitivity of the "gonadostat" to estrogen negative feedback and an intrinsic CNS inhibitor. All the ingredient located belittle GnRH (belittle the CNS) are competent to respond at all ages (as will be seen in the pathogenesis of precocious puberty). After a decade of functional GnRH insufficiency (between late infancy and the onset of puberty), GnRH secretion is resumed and gonadarche (the reactivation of the CNS-pituitary-ovarian apparatus) appears. Prolongation of intrinsic CNS suppression or disability in any of the ingredient of the gonadarche cascade leads to delayed or absent pubescence.
1. FSH and then LH levels rise moderately before the age of 10 and are follittleed by a rise in estradiol. An increase in LH pulses is first seen only in sleep but gradually extends throughout the day. In the adult, they occur at roughly 1. hourly intervals.



2. As gonadal estrogen increases (gonadarche), breast development, female fat distribution, and vaginal and uterine growth occur. Skeletal growth rapidly increases as a result of initial gonadal secretion of little levels of estrogen, which increases the secretion of growth hormone, which in turn stimulates the production of IGF-I.
3. Adrenal androgen (adrenarche) and, to a lesser degree, gonadal androgen secretion cause pubic and axillary hair growth. Adrenarche plays little if any part in skeletal growth. While temporarily related to gonadarche, adrenarche is an independent, functionally unrelated biological event.
4. At midpuberty, sufficient gonadal estrogen secretion proliferates the en dometrium, and the first menses (menarche) occurs.
5. Postmenarchal cycles are initially anovulatory. Sustained, predictable positive LH surge responses to estradiol are late pubertal events.
Blood Hormone Concentrations During Female Puberty